title: 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 vasodilator-stimulated 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.
authors.affiliation: Institute of Physiology, University of Würzburg, Würzburg, Germany. michaela.kuhn@mail.uni-wuerzburg.de
authors.forename: Michaela
authors.initials: M
authors.lastname: Kuhn
authors.forename: Katharina
authors.initials: K
authors.lastname: Völker
authors.forename: Kristine
authors.initials: K
authors.lastname: Schwarz
authors.forename: Javier
authors.initials: J
authors.lastname: Carbajo-Lozoya
authors.forename: Ulrich
authors.initials: U
authors.lastname: Flögel
authors.forename: Christoph
authors.initials: C
authors.lastname: Jacoby
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.forename: Martin
authors.initials: M
authors.lastname: van Eickels
authors.forename: Stepan
authors.initials: S
authors.lastname: Gambaryan
authors.forename: Michael
authors.initials: M
authors.lastname: Hartmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Werner
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schrader
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000209:etiology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000502:physiology; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D006162:Guanylate Cyclase / Q000502:physiology*; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000503:physiopathology; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000502:physiology*; D018919:Neovascularization, Physiologic; D010750:Phosphoproteins / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D015424:Reperfusion; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D000098662:Vasodilator-Stimulated Phosphoprotein; D020097:Natriuretic Peptide, Brain; D048051:p38 Mitogen-Activated Protein Kinases; D006162:Guanylate Cyclase