The natriuretic peptide/guanylyl cyclase–A system functions as a stress-responsive regulator of angiogenesis in mice

Abstract

Cardiac atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) modulate blood pressure and volume by activation of the receptor guanylyl cyclase-A (GC-A) and subsequent intracellular cGMP formation.Here we report what we believe to be a novel function of these peptides as paracrine regulators of vascular regeneration. In mice with systemic deletion of the GC-A gene, vascular regeneration in response to critical hind limb ischemia was severely impaired. Similar attenuation of ischemic angiogenesis was observed in mice with conditional, endothelial cell-restricted GC-A deletion (here termed EC GC-A KO mice). In contrast, smooth muscle cell-restricted GC-A ablation did not affect ischemic neovascularization. Immunohistochemistry and RT-PCR revealed BNP expression in activated satellite cells within the ischemic muscle, suggesting that local BNP elicits protective endothelial effects. Since within the heart, BNP is mainly induced in cardiomyocytes by mechanical load, we investigated whether the natriuretic peptide/GC-A system also regulates angiogenesis accompanying load-induced cardiac hypertrophy. EC GC-A KO hearts showed diminished angiogenesis, mild fibrosis, and diastolic dysfunction. In vitro BNP/GC-A stimulated proliferation and migration of cultured microvascular endothelia by activating cGMP-dependent protein kinase I and phosphorylating vasodilatorstimulated phosphoprotein and p38 MAPK. We therefore conclude that BNP, produced by activated satellite cells within ischemic skeletal muscle or by cardiomyocytes in response to pressure load, regulates the regeneration of neighboring endothelia via GC-A. This paracrine communication might be critically involved in coordinating muscle regeneration/hypertrophy and angiogenesis.

Intramyocardial BNP Gene Delivery Improves Cardiac Function Through Distinct Context-Dependent Mechanisms

“…35 Furthermore, in a pressure overload-induced hypertrophy model, selective disruption of the endothelial GC-A shows diminished angiogenesis. 34 Our present results extend these studies by identifying BNP for the first time as a coronary angiogenic factor. BNP is among the earliest cardiac factors induced in response to hemodynamic load, 6 and this mechanical stretch-induced activation of BNP gene expression is mediated by GATA.…”

“…39,40 Interestingly, the effects of NPs are not mediated by the endothelial release of VEGF-A and autocrine/paracrine activation of the VEGF receptor in vitro in endothelial cell cultures. 34 Our results demonstrate that BNP gene delivery significantly improved LV systolic function after infarction, suggesting that the enhancement of BNP function selectively in the heart may be a potential new therapy after MI. Because growing evidence indicates that the loss of functional capil- laries and microvessels is a critical determinant of myocardial remodeling, 41 we investigated whether BNP has an impact on myocardial angiogenesis.…”

“…In vitro, BNP/GC-A stimulates proliferation and migration of cultured microvascular endothelial cells by activating cGMPdependent protein kinase I. 34 An increase in circulating BNP levels resulting from targeted overexpression of the BNP gene in the liver of mice accelerated vascular regeneration in a limb ischemia model. 35 Furthermore, in a pressure overload-induced hypertrophy model, selective disruption of the endothelial GC-A shows diminished angiogenesis.…”

“…Recently, BNP has been reported to provoke in vitro in cultured microvascular endothelia a mild but significant increase in the levels of phosphorylated p38 MAPK within 15 minutes. 34 In addition, ANP increases p38 MAPK activity in vivo within 20 minutes in the liver, 49 whereas in human umbilical vein endothelial cells, ANP induces inhibition of p38 MAPK through activation of its upstream regulator, the MAPK phosphatase-1. 50 The reason for these discrepant findings may be the differences in experimental settings, and clearly more studies are necessary to better understand the role of p38 MAPK in mediating the effects of the NPs on cardiac function.…”

A Phosphodiesterase-5 Inhibitor Vardenafil Enhances Angiogenesis Through a Protein Kinase G–Dependent Hypoxia-Inducible Factor-1/Vascular Endothelial Growth Factor Pathway

“…The difference in the inhibitory responses between ODQ and DT-3, although it was modest, may be derived from the existence and function of a natriuretic peptides/receptorlinked GC pathway, which is another cGMP/PKG-activating pathway. 3,29 Numerous studies have revealed that circulating EPCs mobilized from BM significantly contribute to angiogenesis in ischemic tissue. 8 Although the mobilization of EPCs from BM is a complex mechanism, it has been suggested that both eNOS expression and local secretion of metalloproteinase-9, a downstream activator of NO, in BM are essential for the mobilization of EPCs.…”