The natriuretic peptide/guanylyl cyclase--a system functions as a stress-responsive regulator of angiogenesis in mice.
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.
Kuhn
Michaela
M
Institute of Physiology, University of Würzburg, Würzburg, Germany. michaela.kuhn@mail.uni-wuerzburg.de
Völker
Katharina
K
Schwarz
Kristine
K
Carbajo-Lozoya
Javier
J
Flögel
Ulrich
U
Jacoby
Christoph
C
Stypmann
Jörg
J
van Eickels
Martin
M
Gambaryan
Stepan
S
Hartmann
Michael
M
Werner
Matthias
M
Wieland
Thomas
T
Schrader
Jürgen
J
Baba
Hideo A
HA
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
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