This Article Full Text Full Text (PDF) All Versions of this Article: 29/10/1516    most recent ATVBAHA.109.187526v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Tokudome, T. Articles by Kangawa, K. PubMed PubMed Citation Articles by Tokudome, T. Articles by Kangawa, K.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1516.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Impaired Recovery of Blood Flow After Hind-Limb Ischemia in Mice Lacking Guanylyl Cyclase-A, a Receptor for Atrial and Brain Natriuretic Peptides

Takeshi Tokudome; Ichiro Kishimoto; Kenichi Yamahara; Tsukasa Osaki; Naoto Minamino; Takeshi Horio; Kazutomo Sawai; Yuhei Kawano; Mikiya Miyazato; Masataka Sata; Masakazu Kohno; Kazuwa Nakao; Kenji Kangawa

From the Research Institute (T.T., I.K., K.Y., T.O., N.M., K.S., M.M., K.K.) and Department of Medicine (T.H., Y.K.), National Cardiovascular Center, Suita, Osaka, Japan; the Department of Cardiovascular Medicine (M.S.), Institute of Health Biosciences The University of Tokushima Graduate School, Tokushima, Japan; the Department of Cardiorenal and Cerebrovascular Medicine (M.K.), Kagawa University Faculty of Medicine, Kagawa, Japan; and the Department of Medicine and Clinical Science (K.N.), Kyoto University Graduate School of Medicine, Kyoto, Japan.

Correspondence to Ichiro Kishimoto, MD, PhD, Division of Biochemistry, National Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail kishimot{at}ri.ncvc.go.jp

Objective— Atrial and brain natriuretic peptides (ANP and BNP, respectively) function via guanylyl cyclase (GC)-A, resulting in diuresis, natriuresis, and blood vessel dilation. Here, we investigated the role of endogenous ANP/BNP-GC-A signaling on reparative vascular remodeling using a hind-limb ischemia model.

Methods and Results— In GC-A–deficient mice (GC-A-KO), hind-limb ischemia resulted in autoamputation or severe ulcers in 60% of mice (6/10) during the 28-day observation period. In wild-type (WT) mice, partial amputation or mild ulcers were detected in only 20% of mice (2/10). Laser Doppler perfusion imaging revealed that the recovery of blood flow in the ischemic limb was significantly inhibited in GC-A-KO mice compared with WT mice. Immunostainings with anti–PECAM-1 antibody demonstrated that, in GC-A-KO, the capillary density of the ischemic tissue was significantly diminished compared to WT. Furthermore, bone marrow transplantation showed the predominant role of GC-A on local ischemic tissue rather than on vascular progenitor cells mobilized from bone marrow during vascular remodeling. In cultured human endothelial cells, ANP treatment significantly stimulated mRNA expressions of vascular endothelial growth factor and endothelial nitric oxide synthase via Erk1/2-dependent mechanism.

Conclusion— These results suggest that endogenous ANP and BNP play important roles in reparative vascular remodeling in ischemic tissue.

We examined the involvement of endogenous ANP and BNP in vascular remodeling after hind-limb ischemia using mice deficient for the guanylyl cyclase-A receptor (GC-A-KO). Blood flow recovery was significantly inhibited in GC-A-KO mice compared with wild-type mice, suggesting endogenous ANP and BNP play important roles in vascular remodeling.

Key Words: atrial natriuretic peptide • brain natriuretic peptide • guanylyl cyclase-A • ischemia • mice