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Research Interests: Chemistry, Medicine, Extracellular Matrix, Angiogenesis, Humans, and 3 moreIschemia, Pubmed, and proteolysis
The ability of organisms to spontaneously develop collateral vessels represents an important response to vascular occlusive diseases that determines the severity of residual tissue ischemia. Neovascularization of ischemic cardiac or... more
The ability of organisms to spontaneously develop collateral vessels represents an important response to vascular occlusive diseases that determines the severity of residual tissue ischemia. Neovascularization of ischemic cardiac or skeletal muscle may be sufficient to preserve tissue integrity and/or function, and may thus be considered to be therapeutic. Innovative gene technologies and advances in animal modeling have enabled research scientists to develop therapeutic angiogenesis strategies applied in animal models of limb or myocardial ischemia and in treatment of patients with peripheral vascular obstruction or coronary artery diseases. Several therapeutic strategies have been proposed and tested even at the clinical level. Recent studies have established the feasibility of using recombinant angiogenic growth factors (mainly VEGF and FGF) to enhance angiogenesis in patients with limb or myocardial ischemia. Angiogenesis therapies using cells as a support for growth factor deli...
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In embryogenesis, the vascular system develops from vasculogenesis in which endothelial cell precursors (angioblasts) differentiate into endothelial cells to form primitive capillary network. The subsequent growth, expansion and... more
In embryogenesis, the vascular system develops from vasculogenesis in which endothelial cell precursors (angioblasts) differentiate into endothelial cells to form primitive capillary network. The subsequent growth, expansion and remodeling of these primitive vessels into a mature vascular network is referred to as angiogenesis. However, a large body of evidence underscores that both vasculogenesis and angiogenesis also proceed in the adult during pathological conditions such as tumor growth or ischemic diseases. The ability of organisms to spontaneously develop collateral vessels represents an important response to vascular occlusive diseases which determine the severity of residual tissue ischemia. Neovascularization of ischemic cardiac or skeletal muscle may be sufficient to preserve tissue integrity and/or function, and may thus be considered to be therapeutic. In addition, under certain circumstances, including advanced age, diabetes, hypertension and hypercholesterolemia such native angiogenesis is impaired leading to the development of disabling symptoms related to tissue ischemia and supporting the requirement of vascular surgery or therapeutic strategies designed to increase native blood vessel growth. Therefore, understanding the mechanisms of the neovascularization process is of major importance. Numerous factors modulated the angiogenic reaction. Among these factors, Angiotensin II (Ang II) the biological active component of the renin-angiotensin system (RAS) might be involved in both beneficial angiogenesis and pathological vessel growth. This chapter focuses on the role of Ang II in angiogenic process mainly in the setting of ischemia.
Research Interests: Stem Cells, Inflammation, Vascular Surgery, Medicine, Cell Differentiation, and 13 moreHumans, Renin Angiotensin Aldosterone System, Animals, Vascular endothelium, System Development, Skeletal Muscle, Endothelial cell, Biological activity, Angiotensin II, Tumor Growth, Angiotensin Converting Enzyme Inhibitors, Blood Vessel, and Bone Marrow Cells
This article summarizes the main mechanisms responsible for the ischemia-induced neovascularization. Growth factors and inflammatory agents are the most powerful actors in the neo-vascularization process. Numerous other factors have been... more
This article summarizes the main mechanisms responsible for the ischemia-induced neovascularization. Growth factors and inflammatory agents are the most powerful actors in the neo-vascularization process. Numerous other factors have been shown to modulate blood vessel growth. Among these, we have tested the potential effect of angiotensin II in several in vivo models of angiogenesis. Angiotensin II has pro-angiogenic effects via its AT1 subtype receptor whereas the AT2 angiotensin II receptor has pro-apoptotic and anti-angiogenic properties. Besides its effect on angiotensin II formation, some angiotensin-converting-enzyme inhibitors have pro-angiogenic effect by increasing the local concentration of bradykinin in ischemic tissues and, thus, by activation of its B2 receptor and then NO release. These besides the "classical" gene and cellular therapies designed for the treatment of pathological tissue ischemia, alternative strategies using new pharmacological properties of ...
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Ischemic disease represents the new epidemic worldwide. Animal models of ischemic disease are useful because they can help us to understand the underlying pathogenetic mechanisms and develop new therapies. The present review article... more
Ischemic disease represents the new epidemic worldwide. Animal models of ischemic disease are useful because they can help us to understand the underlying pathogenetic mechanisms and develop new therapies. The present review article summarizes the results of a consensus conference on the status and future development of experimentation in the field of cardiovascular medicine using murine models of peripheral and myocardial ischemia. The starting point was to recognize the limits of the approach, which mainly derive from species- and disease-related differences in cardiovascular physiology. For instance, the mouse heart beats at a rate 10 times faster than the human heart. Furthermore, healing processes are more rapid in animals, as they rely on mechanisms that may have lost relevance in man. The main objective of the authors was to propose general guidelines, diagnostic end points and relevance to clinical problems.
Research Interests: Atherosclerosis, Medicine, Comorbidity, Humans, Ischemia, and 15 moreConsensus, Mice, Animals, Disease, Animal Model, Animal Experimentation, Mouse Model, Blood Flow, Intensive Care Medicine, Clinical Significance, Murine Model, Extremities, Myocardial Ischemia, guidelines as topic, and Pharmacology and pharmaceutical sciences
Research Interests: Biology, Cell Biology, Medicine, Angiogenesis, Neovascularization, and 15 moreHumans, Ischemia, Mice, Female, Animals, Chemotaxis, Phosphorylation, Protein kinase B, Endothelial cell, Analysis of Variance, Protein Binding, Blood Vessel, Neutralizing antibodies, Milk proteins, and Medical and Health Sciences
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Research Interests: Cardiology, Medicine, Heart Failure, Prospective studies, Humans, and 15 moreInternal Medicine, Congestive Heart Failure, Female, Male, Aspirin, Enzyme, Aged, Middle Aged, Chi Square Distribution, Clopidogrel, Ejection Fraction, Angiotensin Converting Enzyme Inhibitors, Functional Properties, Platelet Aggregation Inhibitors, and Cardiovascular medicine and haematology
The role of endothelin-1 in vascular homeostasis is not yet clearly established. We investigated the responses to phenylephrine and acetylcholine in rat mesenteric resistance artery and aorta mounted in vitro in myographs after a 2-week... more
The role of endothelin-1 in vascular homeostasis is not yet clearly established. We investigated the responses to phenylephrine and acetylcholine in rat mesenteric resistance artery and aorta mounted in vitro in myographs after a 2-week treatment with endothelin-1 (5 pmol kg(-1) min(-1), n = 8). Systolic arterial blood pressure increased in endothelin-1-treated rats (171 +/- 7 mmHg vs. 196 +/- 6 mmHg, P < 0.05). In the aorta, chronic endothelin-1 significantly increased the dilator response to acetylcholine (maximal dilatation: 76 +/- 3 vs. 86 +/- 3% in control, P < 0.05). Acetylcholine-induced dilatation was decreased by nitric oxide (NO) synthase inhibition with NG-nitro-L-arginine methyl ester (L-NAME 100 micromol/l) and partly restored by cyclooxygenases inhibition (indomethacin, 10 micromol/l). In endothelin-1-treated rats, L-NAME-sensitive acetylcholine dilatation was lower than in the control, but dilator cyclooxygenase product(s) were found instead of constrictor cyclooxygenase product(s). In mesenteric resistance arteries chronic endothelin-1 increased the participation of cyclooxygenase products in acetylcholine-induced dilatation from 10 +/- 2 to 19 +/- 3%. In both types of arteries, phenylephrine-induced contraction was not affected by chronic endothelin-1. Thus chronic endothelin-1 increased the participation of dilator cyclooxygenase product(s) in acetylcholine-induced dilatation in the aorta and the mesenteric resistance arteries.
Research Interests: Endocrinology, Chemistry, Medicine, Internal Medicine, Blood Pressure, and 15 moreAnimals, Male, Acetylcholine, Arterial Blood Pressure, Vasoconstriction, Rats, Endothelin-1, Phenylephrine, Vascular Reactivity, Mesenteric Arteries, Aorta, Vasodilation, Methyl Ester, Vascular Resistance, and Pharmacology and pharmaceutical sciences
Research Interests: Endocrinology, Chemistry, Drug interactions, Medicine, Biological Sciences, and 15 moreIn Vitro, Internal Medicine, Animals, Male, Peptide, CHEMICAL SCIENCES, Rat, Arginine, Angiotensin Converting Enzyme, Angiotensin II, Aorta, Angiotensin Converting Enzyme Inhibitors, Medical and Health Sciences, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
We hypothesized that in vitro treatment of peripheral blood mononuclear cells (PB-MNCs) from diabetic patients with ephrin-B2/Fc (EFNB2) improves their proangiogenic therapeutic potential in diabetic ischemic experimental models. Diabetes... more
We hypothesized that in vitro treatment of peripheral blood mononuclear cells (PB-MNCs) from diabetic patients with ephrin-B2/Fc (EFNB2) improves their proangiogenic therapeutic potential in diabetic ischemic experimental models. Diabetes was induced in nude athymic mice by streptozotocin injections. At 9 weeks after hyperglycemia, 105 PB-MNCs from diabetic patients, pretreated by EFNB2, were intravenously injected in diabetic mice with hindlimb ischemia. Two weeks later, the postischemic neovascularization was evaluated. The mechanisms involved were investigated by flow cytometry analysis and in vitro cell biological assays. Paw skin blood flow, angiographic score, and capillary density were significantly increased in ischemic leg of diabetic mice receiving EFNB2-activated diabetic PB-MNCs versus those receiving nontreated diabetic PB-MNCs. EFNB2 bound to PB-MNCs and increased the adhesion and transmigration of PB-MNCs. Finally, EFNB2-activated PB-MNCs raised the number of circulat...
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Cell-based therapy is a promising approach designed to enhance neovascularization and function of ischemic tissues. Interaction between endothelial and smooth muscle cells regulates vessels development and remodeling and is required for... more
Cell-based therapy is a promising approach designed to enhance neovascularization and function of ischemic tissues. Interaction between endothelial and smooth muscle cells regulates vessels development and remodeling and is required for the formation of a mature and functional vascular network. Therefore, we assessed whether coadministration of endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs) can increase the efficiency of cell therapy. Unilateral hindlimb ischemia was surgically induced in athymic nude mice treated with or without intravenous injection of EPCs (0.5×10 6 ), SMPCs (0.5×10 6 ) and EPCs+SMPCs (0.25×10 6 +0.25×10 6 ). Vessel density and foot perfusion were increased in mice treated with EPCs+SMPCs compared to animals receiving EPCs alone or SMPCs alone ( P <0.001). In addition, capillary and arteriolar densities were enhanced in EPC+SMPC–treated mice compared to SMPC and EPC groups ( P <0.01). We next examined the role of Ang-1/Tie2 s...
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We have previously shown that deficiency in the anti-inflammatory cytokine interleukin-10 (IL-10) is responsible for enhanced angiogenesis after hindlimb ischemia. This study examined the putative involvement of matrix metalloproteinase... more
We have previously shown that deficiency in the anti-inflammatory cytokine interleukin-10 (IL-10) is responsible for enhanced angiogenesis after hindlimb ischemia. This study examined the putative involvement of matrix metalloproteinase (MMP) activation in this process. Ischemia was produced by artery femoral occlusion in both C57BL6 IL-10 +/+ and IL-10 −/− mice. Angiographic vessel density and laser Doppler perfusion data at day 28 showed significant improvement in ischemic/nonischemic leg ratio by, respectively, 1.8-fold and 1.4-fold in IL-10 −/− mice compared with IL-10 +/+ mice. This was associated with an increase in vascular endothelial growth factor (VEGF) protein content in the ischemic hindlimb. Three days after ischemia, gelatin zymography showed a significant increase in both pro- and active forms of MMP-2 and MMP-9 in ischemic hindlimbs of IL-10 −/− mice compared with IL-10 +/+ mice ( P <0.01). This increase in MMP activity in IL-10 −/− mice was completely inhibited b...
Research Interests: Endocrinology, Gene expression, Angiogenesis, Internal Medicine, Capillaries, and 15 moreIschemia, Mice, Animals, Perfusion, Fibroblast Growth Factor, Clinical Sciences, Angiography, Phenylalanine, Circulation, Matrix Metalloproteinases, Blood Flow Velocity, Laser Doppler Flowmetry, Matrix Metalloproteinase, Interleukin, and Cardiovascular medicine and haematology
An experimental model of in situ isolated carotid arteries has been used to evaluate the static mechanical properties of the arterial wall in 12-week-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The effects of... more
An experimental model of in situ isolated carotid arteries has been used to evaluate the static mechanical properties of the arterial wall in 12-week-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The effects of endothelium removal and of local incubation with the converting enzyme inhibitor lisinopril (ICI Pharma 209000) on the carotid compliance (CC) were compared with the effects of total abolition of the vascular smooth muscle tone by potassium cyanide. CC measured for pressures ranging from 50 to 175 mm Hg had maximal values (0.22 +/- 0.07 microliter/mm Hg and 0.13 +/- 0.03 microliter/mm Hg, respectively, for WKY and SHR, p less than 0.001) for pressure values close to the operating pressures in both groups. Maximal values of CC were increased by 35% and 45% in WKY and SHR, respectively, after potassium cyanide poisoning (p less than 0.01). The endothelium removal induced a significant increase in CC compared with their control values (+37%, p less than ...
Research Interests: Endocrinology, Chemistry, Biomechanics, Medicine, In Vitro, and 15 moreInternal Medicine, Animals, Vascular endothelium, Clinical Sciences, Rats, Rat, Circulation, ENDOTHELIUM, Angiotensin Converting Enzyme Inhibitors, Lisinopril, Biomechanical Phenomena, Vascular Resistance, Carotid Arteries, Cardiovascular medicine and haematology, and In Vitro Techniques
A local renin-angiotensin system (RAS) is present in the vasculature and might have an important role in the control of vascular resistance. In order to assess its functional role in the control of vasomotor tone, we investigated the... more
A local renin-angiotensin system (RAS) is present in the vasculature and might have an important role in the control of vascular resistance. In order to assess its functional role in the control of vasomotor tone, we investigated the effect of the RAS of a donor vessel (rat carotid artery) on the diameter of a recipient rat mesenteric resistance artery. Arteries were perfused in series in an arteriograph at a rate of 100 μL/min, under a pressure of 100 mm Hg. The two vessels were superfused in separate organ chambers to which drugs were added. Recipient artery internal diameter was measured continuously. Phenylephrine (0.1 μmol/L) was present in the organ baths throughout the experiments, ensuring a preconstriction of the recipient artery (236±4 to 174±3 μm, n=65 arterial segments from 34 rats). The angiotensin I–converting enzyme inhibitors (ACEIs) cilazapril (1 μmol/L) and captopril (10 μmol/L) inhibited phenylephrine-induced constriction by 30±12% (n=7, P <.001) and 20±8% (n=5...
Research Interests: Endocrinology, Chemistry, Medicine, Internal Medicine, Renin Angiotensin Aldosterone System, and 15 moreAnimals, Male, Perfusion, Clinical Sciences, Rats, Circulation, Losartan, Angiotensin II, Phenylephrine, Captopril, Vascular Resistance, Bradykinin, Arteries, Cardiovascular medicine and haematology, and In Vitro Techniques
Background— The hypoxia-inducible transcription factor (HIF) subunits are destabilized via the O 2 -dependent prolyl hydroxylase domain proteins (PHD1, PHD2, and PHD3). We investigated whether inhibition of PHDs via upregulating HIF might... more
Background— The hypoxia-inducible transcription factor (HIF) subunits are destabilized via the O 2 -dependent prolyl hydroxylase domain proteins (PHD1, PHD2, and PHD3). We investigated whether inhibition of PHDs via upregulating HIF might promote postischemic neovascularization. Methods and Results— Mice with right femoral artery ligation were treated, by in vivo electrotransfer, with plasmids encoding for an irrelevant short hairpin RNA (shRNA) (shCON [control]) or specific shRNAs directed against HIF-1α (shHIF-1α), PHD1 (shPHD1), PHD2 (shPHD2), and PHD3 (shPHD3). The silencing of PHDs induced a specific and transient downregulation of their respective mRNA and protein levels at day 2 after ischemia and, as expected, upregulated HIF-1α. As a consequence, 2 key hypoxia-inducible proangiogenic actors, vascular endothelial growth factor-A and endothelial nitric oxide synthase, were upregulated at the mRNA and protein levels. In addition, monocyte chemotactic protein-1 mRNA levels and ...
Research Interests: Inflammation, Macrophages, Medicine, Gene Silencing, Signal Transduction, and 15 moreNeovascularization, Ischemia, Mice, Animals, Plasmids, Clinical Sciences, Public health systems and services research, Circulation, Chemokines, Femoral Artery, Arteriogenesis, Signaling pathway, Genetic Therapy, Endothelial nitric oxide synthase, and Cardiovascular medicine and haematology
Background— C/EBP homologous protein-10 (CHOP-10) is a novel developmentally regulated nuclear protein that emerges as a critical transcriptional integrator among pathways regulating differentiation, proliferation, and survival. In the... more
Background— C/EBP homologous protein-10 (CHOP-10) is a novel developmentally regulated nuclear protein that emerges as a critical transcriptional integrator among pathways regulating differentiation, proliferation, and survival. In the present study, we analyzed the role of CHOP-10 in postnatal neovascularization. Methods and Results— Ischemia was induced by right femoral artery ligation in wild-type and CHOP-10 −/− mice. In capillary structure of skeletal muscle, CHOP-10 mRNA and protein levels were upregulated by ischemia and diabetes mellitus. Angiographic score, capillary density, and foot perfusion were increased in CHOP-10 −/− mice compared with wild-type mice. This effect was associated with a reduction in apoptosis and an upregulation of endothelial nitric oxide synthase (eNOS) levels in ischemic legs of CHOP-10 −/− mice compared with wild-type mice. In agreement with these results, eNOS mRNA and protein levels were significantly upregulated in CHOP-10 short interfering RNA–...
Research Interests: Endocrinology, Biology, Medicine, Humans, Internal Medicine, and 12 moreMice, Animals, Clinical Sciences, Nitric Oxide Synthase, Public health systems and services research, Circulation, Experimental Diabetes Mellitus Type 1 and 2, Protein Binding, Knockout Mice, Femoral Artery, ENOS, and Cardiovascular medicine and haematology
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Research Interests: Endocrinology, Cardiovascular, Enzyme Inhibitors, Medicine, Internal Medicine, and 15 moreHypertension, Animals, Male, Acetylcholine, Mechanical Stress, Rats, Receptor, Muscle contraction, Phenylephrine, Mesenteric Arteries, Blockade, Indomethacin, Endothelin Receptor, Cardiovascular medicine and haematology, and In Vitro Techniques
Background—We investigated the putative proangiogenic activity and molecular pathway(s) of the tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) in a model of surgically induced hindlimb ischemia.Methods and Results—Hindlimb ischemia was... more
Background—We investigated the putative proangiogenic activity and molecular pathway(s) of the tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) in a model of surgically induced hindlimb ischemia.Methods and Results—Hindlimb ischemia was induced by femoral artery ligature and an osmotic minipump was implanted subcutaneously to deliver low (0.12 mg/kg per day) or high (1.2 mg/kg per day) doses of AcSDKP, for 7 or 21 days. Angiography scores, arteriole density, capillary number, and foot perfusion were increased at day 21 in the high-dose AcSDKP-treated mice (by 1.9-, 1.8-, 1.3-, and 1.6-fold, respectively) compared with control animals (P<0.05,P<0.01,P<0.01, respectively). AcSDKP treatment for 24 hours upregulated the monocyte chemoattractant protein-1 (MCP-1) mRNA and protein levels by 1.5-fold in cultured endothelial cells (P<0.01). In the ischemic hindlimb model, administration of AcSDKP also enhanced MCP-1 mRNA levels by 90-fold in ischemic leg (P<0.001) and MCP-1 pla...
Research Interests: Endocrinology, Vascular biology, Medicine, Signal Transduction, Neovascularization, and 15 moreCell Differentiation, Internal Medicine, Ischemia, Mice, Animals, Vascular endothelium, Perfusion, Chemotaxis, Clinical Sciences, Monocytes, Bone Marrow Cells, Femoral Artery, Arteriogenesis, Monocyte, and Cardiovascular medicine and haematology
Objective— Leukocyte infiltration in ischemic areas is a hallmark of myocardial infarction, and overwhelming infiltration of innate immune cells has been shown to promote adverse remodeling and cardiac rupture. Recruitment of inflammatory... more
Objective— Leukocyte infiltration in ischemic areas is a hallmark of myocardial infarction, and overwhelming infiltration of innate immune cells has been shown to promote adverse remodeling and cardiac rupture. Recruitment of inflammatory cells in the ischemic heart depends highly on the family of CC-chemokines and their receptors. Here, we hypothesized that the chemokine decoy receptor D6, which specifically binds and scavenges inflammatory CC-chemokines, might limit inflammation and adverse cardiac remodeling after infarction. Methods and Results— D6 was expressed in human and murine infarcted myocardium. In a murine model of myocardial infarction, D6 deficiency led to increased chemokine (C-C motif) ligand 2 and chemokine (C-C motif) ligand 3 levels in the ischemic heart. D6-deficient (D6 −/−) infarcts displayed increased infiltration of pathogenic neutrophils and Ly6Chi monocytes, associated with strong matrix metalloproteinase-9 and matrix metalloproteinase-2 activities in the ...
Research Interests: Biology, Inflammation, Medicine, Humans, Mice, and 15 moreAnimals, Chemotaxis, Clinical Sciences, Chemokine, Immune system, Bone Marrow Transplantation, Genotype, Myocardial Infarction, Monocytes, Ischemic Heart Disease, Chemokines, Leukocytes, Matrix Metalloproteinase, Cardiovascular medicine and haematology, and Inflammation Mediators
Research Interests: Biology, Medicine, Transplantation, Neovascularization, Cell Differentiation, and 11 moreInternal Medicine, Diabetes mellitus, Ischemia, Mice, Animals, Angiography, Bone Marrow Transplantation, Experimental Diabetes Mellitus Type 1 and 2, Bone Marrow Cells, Laser Doppler Flowmetry, and Medical and Health Sciences
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Research Interests: Biology, Medicine, Cell line, Humans, Ischemia, and 15 moreMice, Electroporation, Animals, Male, Cell Death, Glycoproteins, Clinical Sciences, Angiography, Circulation, Disease Progression, Knockout Mice, Bone Marrow Cells, Laser Doppler Flowmetry, Interleukin, and Cardiovascular medicine and haematology
Cerebrovascular impairment is frequent in patients with Alzheimer disease and is believed to influence clinical manifestation and severity of the disease. Cardiovascular risk factors, especially hypertension, have been associated with... more
Cerebrovascular impairment is frequent in patients with Alzheimer disease and is believed to influence clinical manifestation and severity of the disease. Cardiovascular risk factors, especially hypertension, have been associated with higher risk of developing Alzheimer disease. To investigate the mechanisms underlying the hypertension, Alzheimer disease cross talk, we established a mouse model of dual pathology by infusing hypertensive doses of angiotensin II into transgenic APPPS1 mice overexpressing mutated human amyloid precursor and presenilin 1 proteins. At 4.5 months, at the early stage of disease progression, only hypertensive APPPS1 mice presented impairment of temporal order memory performance in the episodic-like memory task. This cognitive deficit was associated with an increased number of cortical amyloid deposits (223±5 versus 207±5 plaques/mm(2); P<0.05) and a 2-fold increase in soluble amyloid levels in the brain and in plasma. Hypertensive APPPS1 mice presented s...
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Research Interests: Depression, Biology, Immunohistochemistry, Macrophages, Medicine, and 15 moreAngiogenesis, Collagen, Mice, Female, Animals, Laboratory, Clinical Sciences, Isoenzymes, Combination drug therapy, Imidazoles, Benzimidazoles, Angiotensin II, Laminin, Drug combinations, and Angiotensin Receptor Antagonists
After the onset of ischemia, cardiac or skeletal muscle undergoes a continuum of molecular, cellular, and extracellular responses that determine the function and the remodeling of the ischemic tissue. Hypoxia-related pathways,... more
After the onset of ischemia, cardiac or skeletal muscle undergoes a continuum of molecular, cellular, and extracellular responses that determine the function and the remodeling of the ischemic tissue. Hypoxia-related pathways, immunoinflammatory balance, circulating or local vascular progenitor cells, as well as changes in hemodynamical forces within vascular wall trigger all the processes regulating vascular homeostasis, including vasculogenesis, angiogenesis, arteriogenesis, and collateral growth, which act in concert to establish a functional vascular network in ischemic zones. In patients with ischemic diseases, most of the cellular (mainly those involving bone marrow-derived cells and local stem/progenitor cells) and molecular mechanisms involved in the activation of vessel growth and vascular remodeling are markedly impaired by the deleterious microenvironment characterized by fibrosis, inflammation, hypoperfusion, and inhibition of endogenous angiogenic and regenerative progr...
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Research Interests: Hematopoietic Stem Cells, Humans, Blood Pressure, Diuretics, Chronic Disease, and 15 moreFemale, Animals, Bone marrow, Genotype, Adult, Cardiovascular Risk Factor, Combination drug therapy, Cross Sectional Studies, Angiotensin Converting Enzyme Inhibitors, Blood Vessel, Creatinine, Femoral Artery, hyperhomocysteinemia, Endothelial nitric oxide synthase, and Antihypertensive agents
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A gene polymorphism of preproendothelin-1 (a G-to-T transversion that predicts a Lys/Asn change at codon 198) associated with an increased risk of hypertension has been recently described in patients carrying the T allele. No study has... more
A gene polymorphism of preproendothelin-1 (a G-to-T transversion that predicts a Lys/Asn change at codon 198) associated with an increased risk of hypertension has been recently described in patients carrying the T allele. No study has yet determined the impact of this polymorphism on vascular reactivity, although a functional role for endothelin-1 in the pathophysiology of hypertension has been clarified. At subthreshold concentrations, endothelin-1 and angiotensin II induce a potentiation of α-adrenergic–dependent vascular tone caused by an increased sensitivity of the contractile apparatus to calcium. We investigated phenylephrine-induced tone and its amplification by endothelin-1 and angiotensin II in human mammary artery rings in vitro. Contractions to phenylephrine (0.1 to 100 μmol) and endothelin-1 (0.1 to 300 nmol) were not significantly different in rings from GT/TT (n=27) and GG (n=21) patients. A subthreshold concentration of endothelin-1 (10 pmol) potentiated a phenyleph...
Research Interests: Endocrinology, Medicine, Humans, Internal Medicine, Hypertension, and 15 moreFemale, Male, Acetylcholine, Clinical Sciences, Aged, Middle Aged, Gene Polymorphism, Genotype, Angiotensin II, Blood Vessel, Endothelins, nitroprusside, Drug synergism, Cardiovascular medicine and haematology, and In Vitro Techniques
We analyzed the effect of hypertension on postischemic vasculogenesis. Ischemia was induced by right femoral artery ligature in Wistar Kyoto rats (WKY) or spontaneously hypertensive rats (SHR) treated with or without... more
We analyzed the effect of hypertension on postischemic vasculogenesis. Ischemia was induced by right femoral artery ligature in Wistar Kyoto rats (WKY) or spontaneously hypertensive rats (SHR) treated with or without angiotensin-converting enzyme inhibitor (Perindopril, 0.76 mg/kg/d) and angiotensin type 1 receptor blocker (losartan, 30 mg/kg/d). Basal postischemic neovascularization was reduced in SHR compared to WKY ( P <0.05, n=8). Treatment with ACE inhibitor or angiotensin type 1 receptor blocker decreased blood pressure levels by 1.4- and 1.3-fold ( P <0.001), respectively and restored vessel growth in SHR to WKY levels. Interestingly, 14 days after bone-marrow mononuclear cell (BM-MNC) transfusion, angiographic scores, capillary density, and foot perfusion were decreased by 1.4-, 1.5-, and 1.2-fold, respectively in SHR transfused with BM-MNCs isolated from SHR compared to those receiving BM-MNCs of WKY ( P <0.05, n=6). Alteration in BM-MNCs proangiogenic potential wa...
Research Interests: Endocrinology, Medicine, Cell Differentiation, Internal Medicine, Hypertension, and 15 moreIschemia, Blood Pressure, Animals, Male, Bone marrow, Clinical Sciences, Hydralazine, Angiotensin Converting Enzyme, Losartan, ACE Inhibitor, Bone Marrow Cells, Lisinopril, Antihypertensive agents, Ligation, and Cardiovascular medicine and haematology
Research Interests: Endocrinology, Medicine, Internal Medicine, Hypertension, Animals, and 14 moreAcetylcholine, Perfusion, Shear Stress, Phenotype, Clinical Sciences, Rats, Nitric Oxide Synthase, Mesenteric Arteries, Vasodilation, Spontaneously Hypertensive Rat, Methyl Ester, cyclic GMP, Sodium Nitroprusside, and Cardiovascular medicine and haematology
Research Interests: Cardiology, Heart Failure, Enalapril, Blood Pressure, Aldosterone, and 15 moreChronic Disease, Female, Heart rate, Heart, Aspirin, Aged, Adult, Chronic Heart Failure, Angiotensin Converting Enzyme Inhibitors, ACE Inhibitor, Functional Properties, Augmentation Index, Arteries, Diastole, and Cardiovascular medicine and haematology
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Blood pressure is controlled by a complex combination of processes that influence cardiac output and peripheral vascular resistance. Multiple genes potentially influence each parameter involved in the control of blood pressure, and... more
Blood pressure is controlled by a complex combination of processes that influence cardiac output and peripheral vascular resistance. Multiple genes potentially influence each parameter involved in the control of blood pressure, and individuals with the same blood pressor level do not necessarily have the same genotype at relevant loci, nor do individuals with the same genotype at particular loci necessarily have the same blood pressure. Nevertheless, pharmacogenetic studies of vascular reactivity will certainly allow the analysis of the mechanisms affected by genes, and lead to a better understanding of the epidemiologic observations seen in large groups of patients. Polymorphisms in the genes of the renin-angiotensin system allow definition of the &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;genetic profile&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; associated with a higher risk of cardiovascular disease, and can also be linked to significant changes in vascular reactivity in arteries isolated from patients carrying the polymorphisms.
Research Interests: Genetics, Polymorphism, Cardiovascular disease, Medicine, Humans, and 15 moreInternal Medicine, Hypertension, Blood Pressure, Renin Angiotensin Aldosterone System, Genotype, Nitric Oxide Synthase, Cardiac Output Monitoring, Genetic Polymorphism, Blood Vessels, Cardiovascular Diseases, Angiotensin II, Vascular Reactivity, Endothelins, Cardiac output, and Pharmacology and pharmaceutical sciences(Internal Medicine, Hypertension, Blood Pressure, Renin Angiotensin Aldosterone System, Genotype, Nitric Oxide Synthase, Cardiac Output Monitoring, Genetic Polymorphism, Blood Vessels, Cardiovascular Diseases, Angiotensin II, Vascular Reactivity, Endothelins, Cardiac output, and Pharmacology and pharmaceutical sciences)
(Internal Medicine, Hypertension, Blood Pressure, Renin Angiotensin Aldosterone System, Genotype, Nitric Oxide Synthase, Cardiac Output Monitoring, Genetic Polymorphism, Blood Vessels, Cardiovascular Diseases, Angiotensin II, Vascular Reactivity, Endothelins, Cardiac output, and Pharmacology and pharmaceutical sciences)
We hypothesized that activation of angiogenesis by chronic hypoxia may affect vascular resistance and, subsequently, blood pressure levels in spontaneously hypertensive rats (SHRs). Five-week-old prehypertensive SHRs and age-matched... more
We hypothesized that activation of angiogenesis by chronic hypoxia may affect vascular resistance and, subsequently, blood pressure levels in spontaneously hypertensive rats (SHRs). Five-week-old prehypertensive SHRs and age-matched normotensive Wistar–Kyoto (WKY) rats (n=8 per group) were maintained under normobaric normoxic or hypoxic (10% O 2 ) conditions for 8 weeks. Three weeks later, the systolic blood pressure was lower by 26% in hypoxic SHRs compared to normoxic SHRs ( P <0.05) and remained at the normoxic WKY level. Total peripheral vascular resistance, calculated as the mean arterial pressure/cardiac output (assessed by ultrasound imaging and Doppler), was 30% lower in hypoxic than in normoxic SHRs ( P <0.001) and returned to WKY levels. Interestingly, chronic hypoxia also significantly reduced systolic blood pressure in adult 12-week-old SHRs with established hypertension; blood pressure was normalized (versus normoxic WKY rats) after 4 weeks of hypoxia. Changes in ...
Research Interests: Skeletal muscle biology, Hypoxia, Medicine, Angiogenesis, Internal Medicine, and 15 moreAnoxia, Hypertension, Hemodynamics, Blood Pressure, Chronic Disease, Animals, Heart, Clinical Sciences, Rats, Rat, Cardiac Output Monitoring, Circulation, Chronic Hypoxia, Cardiac output, and Cardiovascular medicine and haematology
Recent studies have suggested a proangiogenic effect of angiotensin-converting enzyme (ACE) inhibition. We hypothesized that such a proangiogenic effect of ACE inhibition may be mediated, in part, by bradykinin (BK) B 2 -receptor pathway.... more
Recent studies have suggested a proangiogenic effect of angiotensin-converting enzyme (ACE) inhibition. We hypothesized that such a proangiogenic effect of ACE inhibition may be mediated, in part, by bradykinin (BK) B 2 -receptor pathway. This study therefore examined the neovascularization induced by ACE inhibitor treatment in B 2 receptor–deficient mice (B 2 −/− ) in a model of surgically induced hindlimb ischemia. After artery femoral occlusion, wild-type and B 2 −/− mice were treated with or without ACE inhibitor (perindopril, 3 mg/kg/d) for 28 days. Angiogenesis was then quantitated by microangiography, capillary density measurement, and laser Doppler perfusion imaging. The protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) were determined by Western blot. In wild-type animals, vessel density and capillary number in the ischemic leg were raised by 1.8- and 1.4-fold, respectively, in mice treated with ACE inhibitor when compa...
Research Interests: Chemistry, Biology, Capillaries, Blood Pressure, Animals, and 15 moreEnzyme, Clinical Sciences, Blood Flow, Deficiency, Circulation, Angiotensin Converting Enzyme, Deficit, Blood Flow Velocity, Angiotensin Converting Enzyme Inhibitors, ACE Inhibitor, cyclic GMP, Cell count, Endothelial nitric oxide synthase, Antihypertensive agents, and Cardiovascular medicine and haematology(Enzyme, Clinical Sciences, Blood Flow, Deficiency, Circulation, Angiotensin Converting Enzyme, Deficit, Blood Flow Velocity, Angiotensin Converting Enzyme Inhibitors, ACE Inhibitor, cyclic GMP, Cell count, Endothelial nitric oxide synthase, Antihypertensive agents, and Cardiovascular medicine and haematology)
(Enzyme, Clinical Sciences, Blood Flow, Deficiency, Circulation, Angiotensin Converting Enzyme, Deficit, Blood Flow Velocity, Angiotensin Converting Enzyme Inhibitors, ACE Inhibitor, cyclic GMP, Cell count, Endothelial nitric oxide synthase, Antihypertensive agents, and Cardiovascular medicine and haematology)
Rorα is an orphan nuclear receptor. In homozygous staggerer mutant mice (Rora sg/sg ), a deletion within the Rora gene leads to an overexpression of inflammatory cytokines. Because inflammation and hypoxia are 2 key stimuli of... more
Rorα is an orphan nuclear receptor. In homozygous staggerer mutant mice (Rora sg/sg ), a deletion within the Rora gene leads to an overexpression of inflammatory cytokines. Because inflammation and hypoxia are 2 key stimuli of ischemia-induced angiogenesis, we studied the role of Rorα in this setting. Ischemia was induced by ligation of the right femoral artery in C57BL/6 Rora +/+ and Rora sg/sg mice. After 3 and 28 days, angiogenesis was evaluated by microangiography, measurement of capillary density using immunohistochemistry (anti-CD31), and measurement of blood flow by laser Doppler imaging. At day 3, angiographic score and blood flow were similar in Rora sg/sg mice and in Rora +/+ littermates. Conversely, at day 28, Rora sg/sg mice showed a significant 2-fold increase in angiographic score and a 3-fold increase in capillary density within the ischemic hindlimb compared with control. Functionally, this coincided with a significant rise in leg perfusion in Rora sg/sg mice (0.83±0...
Research Interests: Biology, Microcirculation, Immunohistochemistry, Medicine, Capillaries, and 15 moreMutation, Ischemia, Mice, Animals, Male, Clinical Sciences, Blood Flow, Circulation, Blood Flow Velocity, Laser Doppler Flowmetry, Interleukin, Femoral Artery, Arterioles, Ligation, and Cardiovascular medicine and haematology
Research Interests: Biology, Immunohistochemistry, Apoptosis, Medicine, Angiogenesis, and 15 moreCapillaries, Ischemia, Mice, Animals, Male, Cell Death, Clinical Sciences, Circulation, Angiotensin II, Laser Doppler Flowmetry, angiopoietin, Endothelial nitric oxide synthase, Angiogenesis inhibitors, Ligation, and Cardiovascular medicine and haematology
Background— We hypothesized that microparticles (MPs) released after ischemia are endogenous signals leading to postischemic vasculogenesis. Methods and Results— MPs from mice ischemic hind-limb muscle were detected by electron microscopy... more
Background— We hypothesized that microparticles (MPs) released after ischemia are endogenous signals leading to postischemic vasculogenesis. Methods and Results— MPs from mice ischemic hind-limb muscle were detected by electron microscopy 48 hours after unilateral femoral artery ligation as vesicles of 0.1- to 1-μm diameter. After isolation by sequential centrifugation, flow cytometry analyses showed that the annexin V + MP concentration was 3.5-fold higher in ischemic calves than control muscles (1392±406 versus 394±180 annexin V + MPs per 1 mg; P <0.001) and came mainly from endothelial cells (71% of MPs are CD 144+ ). MPs isolated from ischemic muscles induced more potent in vitro bone marrow–mononuclear cell (BM-MNC) differentiation into cells with endothelial phenotype than those isolated from control muscles. MPs isolated from atherosclerotic plaques were ineffective, whereas those isolated from apoptotic or interleukin-1β–activated endothelial cells also promoted BM-MNC di...
Research Interests: Electron Microscopy, Flow Cytometry, Medicine, Cell Differentiation, Humans, and 15 moreEndothelial Cells, Ischemia, Mice, Animals, Bone marrow, Clinical Sciences, Microparticles, Endothelial cell, Circulation, Knockout Mice, Enzyme Induction, Hematopoietic Stem Cell Transplantation, Femoral Artery, Ligation, and Cardiovascular medicine and haematology
Background— We analyzed the role of aldosterone in ischemia-induced neovascularization and the involvement of angiotensin II (Ang II) signaling in this effect. Methods and Results— Ischemia was induced by right femoral artery ligature in... more
Background— We analyzed the role of aldosterone in ischemia-induced neovascularization and the involvement of angiotensin II (Ang II) signaling in this effect. Methods and Results— Ischemia was induced by right femoral artery ligature in mice treated or not with aldosterone (4.5 μg/day), aldosterone plus spironolactone (aldosterone receptor blocker; 20 mg/kg per day), or aldosterone plus valsartan (angiotensin type 1 [AT 1 ] receptor blocker; 20 mg/kg per day). After 21 days, neovascularization was evaluated by microangiography, capillary density measurement, and laser-Doppler perfusion imaging. Protein level of vascular endothelial growth factor (VEGF) was determined by Western blot analysis in hindlimbs. mRNA levels of renin–angiotensin system components were also assessed by semiquantitative reverse transcription–polymerase chain reaction. Angiographic score, capillary number, and foot perfusion were improved in ischemic/nonischemic leg ratio by 1.4-, 1.5-, and 1.4-fold, respecti...
Research Interests: Endocrinology, Medicine, Signal Transduction, Neovascularization, Internal Medicine, and 15 moreIschemia, Mice, Aldosterone, Renin Angiotensin Aldosterone System, Animals, Skin, Clinical Sciences, Public health systems and services research, Circulation, Blood Vessels, Angiotensin Converting Enzyme, Angiotensin II, Protein content, Reverse transcription polymerase chain reaction, and Cardiovascular medicine and haematology(Ischemia, Mice, Aldosterone, Renin Angiotensin Aldosterone System, Animals, Skin, Clinical Sciences, Public health systems and services research, Circulation, Blood Vessels, Angiotensin Converting Enzyme, Angiotensin II, Protein content, Reverse transcription polymerase chain reaction, and Cardiovascular medicine and haematology)
(Ischemia, Mice, Aldosterone, Renin Angiotensin Aldosterone System, Animals, Skin, Clinical Sciences, Public health systems and services research, Circulation, Blood Vessels, Angiotensin Converting Enzyme, Angiotensin II, Protein content, Reverse transcription polymerase chain reaction, and Cardiovascular medicine and haematology)
Research Interests: Stem Cells, Cardiovascular, Biology, Cardiovascular disease, Medicine, and 10 moreAngiogenesis, Stem Cell Transplantation, Cell therapy, Cell Differentiation, Humans, Animals, Cardiovascular Diseases, Vascular Smooth Muscle, Cardiovascular medicine and haematology, and Cell- and tissue-based therapy
Research Interests: Stem Cells, Cardiovascular, Wound Healing, Inflammation, Medicine, and 14 moreSignal Transduction, Inflammatory Immune Response, Tissue repair, Neovascularization, Humans, Endothelial Cells, Ischemia, Animals, Peripheral Vascular Disease, Mechanical Stress, Inflammatory response, Vascular Disease, Cardiovascular medicine and haematology, and Inflammation Mediators
Research Interests:
Objective— We analyzed the beneficial therapeutic effect of angiotensin converting enzyme inhibitor (ACEI) on both retinal and hind limb neovascularization in diabetic mice. Methods and Results— Diabetic mice (streptozotocin, 40 mg/kg)... more
Objective— We analyzed the beneficial therapeutic effect of angiotensin converting enzyme inhibitor (ACEI) on both retinal and hind limb neovascularization in diabetic mice. Methods and Results— Diabetic mice (streptozotocin, 40 mg/kg) were treated with or without ACEI (Perindopril, 3 mg/kg per day) or AT1 receptor blocker (Candesartan, 20 mg/kg) for 4 months. Hind limb ischemia was then induced by right femoral artery ligature for 1 additional month. In the ischemic leg, angiographic score, capillary density, and foot perfusion were increased by 2.7, 2.0-fold, and 1.6-fold, respectively, in ACEI-treated diabetic mice compared with untreated diabetic animals ( P <0.01). ACEI also raised vascular endothelial growth factor (VEGF) protein level by 1.4-fold in ischemic diabetic leg. This ACEI pro-angiogenic effect was totally blunted in diabetic bradykinin B2 receptor-deficient animals, suggesting that it was mediated by the bradykinin pathway. In the diabetic retina, angiotensinogen...
Research Interests: Vascular biology, Angiogenesis, Capillaries, Ischemia, Mice, and 15 moreRenin Angiotensin Aldosterone System, Animals, Retina, Clinical Sciences, Angiography, Body Weight, Angiotensin Converting Enzyme, Streptozotocin, Angiotensin Converting Enzyme Inhibitors, Laser Doppler Flowmetry, Vascular Endothelial Growth Factor, Bradykinin, Streptozocin, Cardiovascular medicine and haematology, and Retinal vessels(Renin Angiotensin Aldosterone System, Animals, Retina, Clinical Sciences, Angiography, Body Weight, Angiotensin Converting Enzyme, Streptozotocin, Angiotensin Converting Enzyme Inhibitors, Laser Doppler Flowmetry, Vascular Endothelial Growth Factor, Bradykinin, Streptozocin, Cardiovascular medicine and haematology, and Retinal vessels)
(Renin Angiotensin Aldosterone System, Animals, Retina, Clinical Sciences, Angiography, Body Weight, Angiotensin Converting Enzyme, Streptozotocin, Angiotensin Converting Enzyme Inhibitors, Laser Doppler Flowmetry, Vascular Endothelial Growth Factor, Bradykinin, Streptozocin, Cardiovascular medicine and haematology, and Retinal vessels)
This study investigated in vivo the putative angiogenic role of endothelin (ET)-1 in a model of ischemia-induced angiogenesis. Ischemia was produced by unilateral femoral artery occlusion in Wistar rats submitted to either chronic ET-1... more
This study investigated in vivo the putative angiogenic role of endothelin (ET)-1 in a model of ischemia-induced angiogenesis. Ischemia was produced by unilateral femoral artery occlusion in Wistar rats submitted to either chronic ET-1 infusion (2 nmol · kg −1 · min −1 ) or to a dual ET A /ET B receptor antagonist (bosentan, 100 mg · kg −1 · d −1 ) for 3 and 28 days. Arterial density was evaluated by microangiography and measurement of capillary and arteriolar density in hindlimb muscles. ET-1 infusion had no effect on ischemia-induced angiogenesis and was associated with a slight decrease in vascular endothelial growth factor (VEGF) content measured by Western blot analysis. Conversely, bosentan induced a marked increase in vessel density at 3 and 28 days (1.4-fold and 1.7-fold, respectively, compared with no treatment; P <0.05), which was associated with an increase in VEGF and endothelial NO synthase levels in ischemic legs (by 31±8% and 45±23%, respectively, at 3 days and by ...
Research Interests: Enzyme Inhibitors, Comparative Study, Medicine, Angiogenesis, Signal Transduction, and 15 moreAntibodies, Capillaries, Ischemia, Nitric oxide, Animals, Male, Exploration, Clinical Sciences, Rats, Nitric Oxide Synthase, Rat, Methyl Ester, Neutralizing antibodies, Sulfonamides, and Cardiovascular medicine and haematology
Research Interests: Enzyme Inhibitors, Medicine, Hypertension, Blood Pressure, Nitric oxide, and 15 moreAnimals, Male, Shear Stress, Arterial Blood Pressure, Clinical Sciences, Pressure, Rats, Time Factors, Rat, Reference Values, Spontaneously Hypertensive Rat, Methyl Ester, Indomethacin, Vascular Resistance, and Cardiovascular medicine and haematology
Objective— Tissue kallikrein (TK) participates in acute flow-induced dilatation (FID) of large arteries. We investigated whether TK deficiency blunts FID and alters chronic flow-related arterial structural and functional changes in... more
Objective— Tissue kallikrein (TK) participates in acute flow-induced dilatation (FID) of large arteries. We investigated whether TK deficiency blunts FID and alters chronic flow-related arterial structural and functional changes in resistance-sized muscular arteries. Methods and Results— Vasomotor responses and structural parameters were determined in uterine arteries isolated from nonpregnant, 18- to 19-day pregnant, and 7-day postpartum TK −/− and TK +/+ littermate mice. In TK −/− mice, values of diameter, medial cross-sectional area (CSA), myogenic tone, and dilatation in response to acetylcholine were comparable to those values in TK +/+ mice, but FID (0 to 100 μL/min) was significantly reduced (55±4% versus 85±4% in TK +/+ mice). In both mouse strains, pregnancy resulted in significant increases in diameter and medial CSA and in the N w -nitro- l -arginine methyl ester–sensitive component of FID. By 7 days after pregnancy, uterine arterial diameter and CSA values no longer diff...