Impaired recovery of blood flow after hind-limb ischemia in mice lacking guanylyl cyclase-A, a receptor for atrial and brain natriuretic peptides.

Abstract

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.

CONCLUSIONS:

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

• Authors: 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
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 29 Issue 10 Pg. 1516-21 (Oct 2009) ISSN: 1524-4636 [Electronic] United States
• PMID: 19628785 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Adhesion Molecules
• Microfilament Proteins
• Phosphoproteins
• RNA, Messenger
• Vascular Endothelial Growth Factor A
• vasodilator-stimulated phosphoprotein
• Natriuretic Peptide, Brain
• Atrial Natriuretic Factor
• Nitric Oxide Synthase Type III
• Extracellular Signal-Regulated MAP Kinases
• Receptors, Atrial Natriuretic Factor
• atrial natriuretic factor receptor A

Topics

• Animals
• Atrial Natriuretic Factor (physiology)
• Blood Vessels (pathology, physiology)
• Cell Adhesion Molecules (physiology)
• Cells, Cultured
• Extracellular Signal-Regulated MAP Kinases (physiology)
• Hindlimb (blood supply)
• Humans
• Ischemia (physiopathology)
• Male
• Mice
• Microfilament Proteins (physiology)
• Natriuretic Peptide, Brain (physiology)
• Nitric Oxide Synthase Type III (genetics)
• Phosphoproteins (physiology)
• RNA, Messenger (analysis)
• Receptors, Atrial Natriuretic Factor (physiology)
• Regeneration
• Regional Blood Flow
• Vascular Endothelial Growth Factor A (genetics)