Hypertension: a disease of the microcirculation?
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Animals↗
Biomedical subjects
Bernard I Levy
Publications and source records attributed to Bernard I Levy.
Increased skin capillary density in treated essential hypertensive patients.
BACKGROUND: Microvascular rarefaction is a hallmark of essential hypertension. We measured the skin capillary density in nondiabetic hypertensive subjects with effective antihypertensive treatment and evaluated possible correlations with arterial blood pressure (BP). METHODS: This cross-sectional observational study included 76 (55 +/- 1 years) consecutive outpatients with essential hypertension under chronic antihypertensive drug treatment (BP < 140/90 mm Hg), 24 age- and sex-matched patients with recently discovered and never-treated hypertension and 70 normotensive (BP < 140/90 mm Hg) age- and sex-matched healthy controls. We used intravital video-microscopy to measure basal and maximal (during venous congestion) skin capillary densities in the dorsum of the fingers. Aortic stiffness was evaluated using pulse wave velocity and central aortic pressure calculated from radial artery applanation tonometry. RESULTS: Baseline and maximal capillary densities (number/mm2) were significantly lower (59.6 +/- 2.0 and 62.0 +/- 1.9) in untreated than in treated hypertensive patients (74.0 +/- 1.4 and 79.4 +/- 1.5; P < .001) and than in normotensives (68.2 +/- 1.5 and 72.4 +/- 1.5; P < .001). Based on multiple regression analysis, after adjustment to tobacco consumption, aortic (and not brachial) systolic BP was inversely correlated with basal and postocclusive capillary densities in normotensive subjects. In hypertensives, this correlation disappears and capillary density was influenced by two independent variables, antihypertensive drug treatment and overweight. CONCLUSIONS: In nondiabetic hypertensive patients, capillary density is reduced in association with a cluster of cardiovascular risk factors involving tobacco consumption and obesity. The finding of an increased capillary density in effectively treated antihypertensives suggests that a cause-to-effect relationship between BP and capillary density should be evaluated in a long-term prospective follow-up.
Antihypertensive Agents↗
NADPH oxidase-derived overproduction of reactive oxygen species impairs postischemic neovascularization in mice with type 1 diabetes.
We hypothesized that diabetes-induced oxidative stress may affect postischemic neovascularization. The response to unilateral femoral artery ligation was studied in wild-type or gp91(phox)-deficient control or type 1 diabetic mice or in animals treated with the anti-oxidant N-acetyl-l-cysteine (NAC) or with in vivo electrotransfer of a plasmid encoding dominant-negative Rac1 (50 microg) for 21 days. Postischemic neovascularization was reduced in diabetic mice in association with down-regulated vascular endothelial growth factor-A protein levels. In diabetic animals vascular endothelial growth factor levels and postischemic neovascularization were restored to nondiabetic levels by the scavenging of reactive oxygen species (ROS) by NAC administration or the inhibition of ROS generation by gp91(phox) deficiency or by administration of dominant-negative Rac1. Finally, diabetes reduced the ability of adherent bone marrow-derived mononuclear cells (BM-MNCs) to differentiate into endothelial progenitor cells. Treatment with NAC (3 mmol/L), apocynin (200 micromol/L), or the p38MAPK inhibitor LY333351 (10 micromol/L) up-regulated the number of endothelial progenitor cell colonies derived from diabetic BM-MNCs by 1.5-, 1.6-, and 1.5-fold, respectively (P < 0.05). In the ischemic hindlimb model, injection of diabetic BM-MNCs isolated from NAC-treated or gp91(phox)-deficient diabetic mice increased neovascularization by approximately 1.5-fold greater than untreated diabetic BM-MNCs (P < 0.05). Thus, inhibition of NADPH oxidase-derived ROS overproduction improves the angiogenic and vasculogenic processes and restores postischemic neovascularization in type 1 diabetic mice.
Animals↗
Thromboxane A2/prostaglandin H2 receptor activation mediates angiotensin II-induced postischemic neovascularization.
OBJECTIVE: We analyzed the involvement of thromboxane (TX) A2/prostaglandin (PG) H2 (TP) receptor in ischemia-induced neovascularization in mice. METHODS AND RESULTS: Unilateral hindlimb ischemia was induced by right femoral artery ligature in male C57BL/6J mice (n=7 per group). Animals were then treated with or without TP receptor antagonist (S18886, 5 or 10 mg/kg per day; ramatroban, 10 mg/kg per day) or aspirin (30 mg/kg per day) in drinking water for 21 days. Hindlimb ischemia raised plasma level of TXB2, the stable metabolite of TXA2, by 4.7-fold. This increase was blocked by aspirin treatment whereas S18886 (5 or 10 mg/kg per day) had no effect. However, neither S 18886 nor aspirin affected postischemic neovascularization. We next assessed the putative involvement of TXA2 signaling in angiotensin II (Ang II) proangiogenic pathway. Ang II (0.3 mg/kg per day) enhanced TXB2 plasma levels by 2.6-fold over that of control (P<0.01). Ang II-induced TXB2 upregulation was reduced by cotreatment with Ang II type I receptor antagonist (candesartan, 20 mg/kg per day). Angiographic score, capillary number, and foot perfusion were improved by 1.7-, 1.7-, and 1.4-fold, respectively, in Ang II-treated mice compared with controls (P<0.05). Ang II proangiogenic effect was associated with a 1.6-fold increase in VEGF-A protein content (P<0.05) and a 1.4-fold increase in the number of Mac-3-positive cells (ie, macrophages) in ischemic areas (P<0.05). Interestingly, treatments with TP receptor antagonists or aspirin hampered the proangiogenic effects of Ang II. CONCLUSIONS: Endogenous activation of TXA2 receptor by eicosanoids did not modulate spontaneous neovascularization in the setting of ischemia. Conversely, TXA2 signaling is involved in Ang II-induced AT1-dependent vessel growth.
Angiotensin II↗
Beneficial effects of circulating progenitor endothelial cells activated by angiotensin receptor antagonists.
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Angiotensin II Type 1 Receptor Blockers↗
Impairment in postischemic neovascularization in mice lacking the CXC chemokine receptor 3.
Inflammatory cell infiltration is a feature of postischemic neovascularization. However, mechanisms leading to leukocyte attraction to the site of neovascularization are still undefined. We hypothesized that the CXC chemokine receptor 3 (CXCR3) may contribute to leukocyte accumulation and subsequently to blood vessel growth in the ischemic area. Ischemia induced by femoral artery ligature improved the number of CXCR3-expressing cells and the level of its ligand, CXCL10. Angiographic score, blood flow recovery measurement, and capillary density analysis showed a significant decrease of ischemic/nonischemic leg ratio in CXCR3-deficient mice when compared with controls (P<0.05), at day 21 after ischemia. Interestingly, this impairment was as important as that observed in mice deficient for the well known CC-chemokine monocyte chemoattractant protein-1 (MCP-1). At day 7 of ischemic injury, the number of CD3-positive T cells and Mac-3-positive monocytes/macrophages was 38% and 45% lower, respectively, in the ischemic leg of CXCR3-deficient mice compared with the control group (P<0.05), suggesting an important role for CXCR3 in leukocyte recruitment into the ischemic area. VEGF protein content, a classical proangiogenic factor, was also markedly reduced (80% reduction) in ischemic leg of CXCR3-deficient mice (P<0.01). Injection of bone marrow-derived mononuclear cells (BM-MNCs) isolated from wild-type animals restored the neovascularization reaction in CXCR3-deficient mice whereas BM-MNCs from CXCR3-deficient mice was ineffective. In conclusion, CXCR3 plays a key role in neovascularization and provides novel information on the mechanisms leading to leukocyte infiltration in the vessel growth area.
Animals↗
High blood pressure reduction reverses angiotensin II type 2 receptor-mediated vasoconstriction into vasodilation in spontaneously hypertensive rats.
BACKGROUND: We have previously shown that angiotensin II type 2 receptor (AT(2)R) stimulation causes endothelium-dependent vasodilation that does not desensitize after chronic angiotensin II type 1 receptor (AT1R) blockade, suggesting a role for AT2R in antihypertensive treatment. METHODS AND RESULTS: We recorded mean arterial pressure (MAP) and investigated AT2R by Western blot analysis, immunohistochemistry, and function in isolated mesenteric resistance arteries (205 microm in diameter) from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) receiving the following for 4 weeks in drinking water: placebo, AT1R blockade (candesartan; 2 mg/kg per day), ACE inhibitor (perindopril; 3 mg/kg per day), nonselective vasodilator (hydralazine; 16 or 24 mg/kg per day), or candesartan plus hydralazine (16 mg/kg per day). In precontracted isolated arteries, AT2R stimulation (angiotensin II in the presence of candesartan) caused vasodilation in WKY rats (MAP=118 mm Hg) and vasoconstriction in SHR (MAP=183 mm Hg). In SHR treated with candesartan (MAP=146 mm Hg) or hydralazine (16 mg/kg per day; MAP=145 mm Hg), AT2R-induced contraction was reduced by 50%. In SHR treated with perindopril (MAP=125 mm Hg), AT2R stimulation induced vasodilation. In SHR treated with hydralazine (24 mg/kg per day; MAP=105 mm Hg) and in SHR treated with hydralazine (16 mg/kg per day) plus candesartan (MAP=102 mm Hg), an AT2R-mediated vasodilation was restored. Immunochemistry and Western blot analysis showed that AT2R expression, lower in SHR than in WKY rats, was restored to normal levels by treatments reducing arterial pressure in SHR. CONCLUSIONS: Our results suggest that in resistance arteries of SHR, (1) AT2R is downregulated by hypertension, and (2) specific and nonspecific antihypertensive treatments restore AT(2)R expression and vasodilator functions.
Animals↗
How to explain the differences between renin angiotensin system modulators.
Angiotensin II (Ang II) plays important roles in the development of cardiovascular diseases including hypertension, renal diseases, cardiac hypertrophy, congestive heart failure, and ischemic heart disease. Angiotensin II exerts classic hemodynamic and renal effects, but it is also a local biologically active mediator with direct effects on endothelial and smooth muscle cells. Two subtypes of Ang II receptors, type 1 (AT(1)) and type 2 (AT(2)), have been identified. Their roles have been investigated in depth in vivo and in vitro, although few data are available concerning the role of the AT(2) receptors in the adult circulation in humans. The two receptors, both of which belong to the superfamily of G-protein-coupled receptors, have different signaling pathways and different functions. The AT(1) receptor subtype is expressed ubiquitously and is involved in most of the well-known biological functions of Ang II. The AT(1) receptor transactivates growth pathways and mediates major Ang II effects such as vasoconstriction, increased cardiac contractility, renal tubular sodium reabsorption, cell proliferation, vascular and cardiac hypertrophy, inflammatory responses, and oxidative stress. In contrast to AT(1), the physiologic role of AT(2) receptors has long remained an enigma. The AT(2) receptors are highly expressed in fetal tissues, although their expression dramatically decreases after birth, being restricted to a few organs, including the cardiovascular system. The AT(2) receptor is re-expressed in the adult animal after cardiac and vascular injury and during wound healing, suggesting a role for this receptor in tissue remodeling, growth, or development. Recent and concordant data suggested that overstimulation of AT(2) receptors might be implied in cardiac and vascular hypertrophic processes. Both Ang II receptors are involved in hypoxia-induced neovascularization. A large set of experimental evidence suggests that activation of the AT(1) receptor results in proangiogenic effects, whereas AT(2) receptors mediate apoptosis and thus antiangiogenic effects. Furthermore, bradykinin through its B(1) or B(2) receptors is a potent activator of experimental hypoxia-induced neovascularization. Thus, pharmacologic blockade of the AT(1) receptor and resulting overactivation of AT(2) receptors could impair or delay neovascularization in ischemic tissues in patients receiving chronic treatment with angiotensin receptor blockers. In contrast, increased tissue bradykinin resulting from inhibition of converting enzyme could help to restore functional vascularization in ischemic tissues. These basic concepts deserve a second reading and reevaluation to discuss differences in vascular protection in large clinical trials with different classes of drugs acting on the renin-angiotensin system.
Angiotensin II Type 1 Receptor Blockers↗
Dual effect of angiotensin-converting enzyme inhibition on angiogenesis in type 1 diabetic mice.
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 and ACE mRNA levels were increased by 2.8-fold and 4.1-fold, respectively (P<0.01 versus nondiabetic mice), highlighting a local activation of renin-angiotensin system. Diabetes also raised VEGF protein level by 1.5-fold (P<0.05 versus nondiabetic mice). Treatments with ACEI and AT1 receptor blocker hampered diabetes-induced VEGF upregulation and retinal neovascularization. CONCLUSIONS: ACE inhibition improved neovascularization in the diabetic ischemic leg through activation of bradykinin signaling, whereas it reduced vessel growth in the diabetic retina through inhibition of overacting Ang II pathway.
Angiography↗
Cyclooxygenase involvement in thromboxane-dependent contraction in rat mesenteric resistance arteries.
The influence of cyclooxygenase pathway activation following thromboxane-endoperoxide (TP) receptor stimulation was studied in rat mesenteric resistance arteries (n=6 to 10 per group). We studied isolated, perfused, and pressurized mesenteric resistance arteries (mean internal diameter 214 microm) using an arteriograph, enabling us to study arteries in physiological conditions of flow and pressure. Changes in diameter were continuously recorded, and contractions measured as internal diameter reduction. Release of cyclooxygenase pathway metabolites was also assessed by enzyme immunoassay (EIA) analysis of mesenteric bed perfusions. The thromboxane A2 (TxA2) analog U-46619 (1 micromol/L) induced a significant contraction (108 microm maximal diameter reduction). Inhibition by 3 chemically different cyclooxygenase inhibitors (ie, flurbiprofen, indomethacin, and aspirin) potently reduced the contraction to 27%, 25%, and 6% of control, respectively. The selective cyclooxygenase-1 inhibitor SC-58560 inhibited U-46619 contraction, whereas selective cyclooxygenase-2 inhibition (SC-58236) had no effect. Thromboxane synthase inhibition (furegrelate) did not affect U-46619-induced contraction, but it was reduced by cytosolic phospholipase A2 inhibition. Measurement of cyclooxygenase derivatives produced by the isolated mesenteric bed showed that PGE2 was produced after TxA2-receptor stimulation with U-46619. Exogenous prostaglandin E2 (in the presence of the TxA2 receptor antagonist SQ 29 548) and U-46619 contracted mesenteric arteries with a similar potency (EC50: 0.30 and 0.48 micromol/L, respectively). This study provides the first evidence that TxA2-receptor-dependent contraction in a resistant artery involved cyclooxygenase stimulation and, at least in part, a PGE2 formation. This mechanism of TxA2-dependent contraction in resistant arteries might be of importance in the understanding of diseases affecting resistant arteries and involving TxA2, such as hypertension.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Aldosterone enhances ischemia-induced neovascularization through angiotensin II-dependent pathway.
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 microg/day), aldosterone plus spironolactone (aldosterone receptor blocker; 20 mg/kg per day), or aldosterone plus valsartan (angiotensin type 1 [AT1] 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, respectively, in aldosterone-treated mice compared with controls (P<0.05). Aldosterone proangiogenic effect was associated with 2.3-fold increase in VEGF protein content (P<0.05). Treatments with spironolactone or with neutralizing VEGF antibody hampered the proangiogenic effect of aldosterone (P<0.05 versus aldosterone-treated mice). Interestingly, AT1 receptor blockade completely abrogated the aldosterone proangiogenic effect, emphasizing the involvement of Ang II-related pathway in aldosterone-induced vessel growth. In this view, angiotensinogen mRNA content was 2.2-fold increased in aldosterone-treated mice in reference to controls (P<0.05), whereas that of renin, angiotensin-converting enzyme, and AT1 receptor subtype was unaffected. Aldosterone treatment also decreased AT2 mRNA content by 2-fold (P<0.05 versus controls), suggesting that aldosterone may switch the Ang II pathway toward activation of vessel growth. CONCLUSIONS: This study shows for the first time that aldosterone increases neovascularization in the setting of ischemia through activation of Ang II signaling.
Aldosterone↗
Angiogenic effect of prostaglandin I 2 in relation with its effect on PPAR nuclear receptors.
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Animals↗
Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases.
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Animals↗
Defect in microvascular adaptation to chronic changes in blood flow in mice lacking the gene encoding for dystrophin.
Dystrophin has a key role in striated muscle mechanotransduction. In mice lacking the gene encoding for dystrophin (mdx mice), the absence of dystrophin and several other proteins of the dystrophin-glycoprotein complex induces a defect in flow (shear stress)-mediated NO-dependent dilation (FMD). Because the endothelium is essential for the adaptation of arteries to chronic changes in blood flow, the long-term consequences of this vascular deficiency might affect flow-induced vascular remodeling. Thus, we submitted mouse mesenteric resistance arteries to chronic changes in flow by alternatively ligating arteries. Arteries were thus submitted to high flow (HF), low flow (LF), or normal flow. After 2 weeks, arteries were studied in vitro in an arteriograph. Increases in diameter (from 174+/-10 to 210+/-15 microm, pressure 75 mm Hg) found in HF arteries were not significant in mdx mice. Arterial diameters in LF arteries decreased similarly in control and mdx mice. FMD increased in HF arteries and decreased in LF arteries. FMD was not increased in HF arteries in mdx mice. NO-dependent FMD and NO synthase expression increased in the HF arteries of control mice but not in those of mdx mice. Dilatory and contractile tone, depending on the smooth muscle, was unaffected in HF arteries but decreased in LF arteries of both strains. We conclude that resistance arteries of mdx mice do not adapt properly to chronic changes in flow, inasmuch as the increases in diameter, endothelial NO synthase expression, and FMD did not occur in mdx mice submitted to HF for 2 weeks. This study suggests that blood flow regulation might be disturbed in dystrophin-related myopathies, possibly increasing organ damage.
Adaptation, Physiological↗
Endothelial nitric oxide synthase lies downstream from angiotensin II-induced angiogenesis in ischemic hindlimb.
We assessed the role of angiotensin (Ang) II in ischemia-induced angiogenesis and analyzed the molecular pathways involved in such an effect. Ischemia was produced by unilateral artery femoral occlusion in control, in valsartan-treated (Ang II receptor type I antagonist, 20 mg/kg per day), in Ang II-treated (5 ng/kg per min), and in Ang II and valsartan-treated rats. After 28 days, angiogenesis was assessed by microangiography and capillary density measurement in hindlimbs. The ischemic/nonischemic leg ratio for angiographic score and capillary number increased by 2.6- and 2-fold, respectively, in Ang II-treated rats compared with controls (P<0.01). This was associated with an increase in vascular endothelial growth factor (VEGF; 1.6-fold) and endothelial NO synthase (eNOS; 1.8-fold) protein content within the ischemic leg, assessed by Western blot. Angiotensin type 1 receptor blockade and administration of VEGF neutralizing antibody (2.5 microg IP, twice a week) in Ang II-treated rats completely prevented such Ang II angiogenic effects. The key role of eNOS was then emphasized by using mice deficient in gene encoding for eNOS. In wild-type mice, Ang II (0.3 mg/kg per min) treatment increased by 1.7- and 1.6-fold the ischemic/nonischemic leg for angiographic score and blood perfusion (assessed by laser Doppler perfusion imaging) ratios, respectively (P<0.01). Conversely, no significant changes were observed in Ang II-treated mice deficient in gene encoding for eNOS. Subhypertensive dose of Ang II enhanced angiogenesis associated with tissue ischemia through angiotensin type 1 receptor activation that involved the VEGF/eNOS-dependent pathway.
Angiotensin II↗
Genetic determinants of vascular reactivity.
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 "genetic profile" 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.
Angiotensin II↗
Mitogen-activated protein kinase cascade, endothelial function and vasomotor tone in the spontaneously hypertensive rat.
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Animals↗
Angiotensin II angiogenic effect in vivo involves vascular endothelial growth factor- and inflammation-related pathways.
Although accumulating lines of evidence indicate the proangiogenic role of angiotensin II (Ang II), little is known about the molecular mechanisms associated with such an effect. This study aimed to identify molecular events involved in Ang II-induced angiogenesis in the Matrigel model in mice. C57Bl/6 female mice received a subcutaneous injection of either Matrigel or Matrigel with Ang II (10(-7) M) alone, with Ang II and an AT1 receptor antagonist (candesartan, 10(-6) M), or with Ang II and AT2 receptor antagonist (PD123319, 10(-6) M). After 14 days, angiogenesis was assessed in the Matrigel-plug by histological evaluation and cellular counting. Ang II increased by 1.9-fold the number of cells within the Matrigel (p < 0.01 versus control). Immunohistological analysis revealed the presence of macrophages, endothelial and smooth muscle cells, and the development of vascular-like structure. Such an angiogenic effect was associated with an increase in vascular endothelial growth factor (VEGF) (1.5-fold, p < 0.01), endothelial nitric oxide (eNOS) (1.7-fold, p < 0.01), and cyclooxygenase-2 (1.4-fold, p < 0.05) protein levels measured by Western blotting. Conversely, Ang II treatment did not affect MMP-9 and MMP-2 activity, assessed by zymography. Blockade of AT1 receptor completely prevented the Ang II-induced angiogenesis and protein regulations, whereas that of AT2 was ineffective. Administration of VEGF neutralizing antibody (2.5 microg ip twice a week) and cyclooxygenase-2 selective inhibitor (nimesulide, 30 mg/L) also hampered Ang II proangiogenic effect. In addition, Ang II-induced cell ingrowth was impaired by treatment with nitric oxide synthase inhibitor (L-NAME, 10 mg/kg/day) and in eNOS-deficient mice. Therefore, in an in vivo model, Ang II induced angiogenesis through AT1 receptor, which involved activation of VEGF/eNOS-related pathway and of the inflammatory process.
Angiotensin II↗