Impaired Recovery of Blood Flow After Hind-Limb Ischemia in Mice Lacking Guanylyl Cyclase-A, a Receptor for Atrial and Brain Natriuretic Peptides
Impaired Recovery of Blood Flow After Hind-Limb Ischemia in Mice Lacking Guanylyl Cyclase-A, a Receptor for Atrial and Brain Natriuretic Peptides
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DOI：
10.1161/atvbaha.109.187526
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发表时间：
2009-10-01
影响因子：
8.7
通讯作者：
Kangawa, Kenji
中科院分区：
文献类型：
--
作者：
Tokudome, Takeshi;Kishimoto, Ichiro;Kangawa, Kenji
心钠素和脑钠素（分别为ANP和BNP）通过鸟苷酸环化酶（GC）-A发挥作用，导致利尿、尿钠排泄和血管扩张。在这里，我们研究了内源性ANP/BNP-GC-A信号传导对修复性血管重塑的作用，使用后肢ischemia.Methods和Results-In GC-A-deficient mice（GC-A-KO），后肢缺血导致自体截肢或严重溃疡的60%的小鼠（6/10）在28天的观察期。在野生型（WT）小鼠中，仅在20%的小鼠（2/10）中检测到部分截肢或轻度溃疡。激光多普勒灌注成像显示，与WT小鼠相比，GC-A-KO小鼠缺血肢体的血流恢复受到显著抑制。用抗PECAM-1抗体的免疫染色证明，在GC-A-KO中，与WT相比，缺血组织的毛细血管密度显著降低。此外，骨髓移植显示GC-A在局部缺血组织中的主导作用，而不是在血管重建期间从骨髓动员的血管祖细胞上。在培养的人内皮细胞，ANP治疗显着刺激血管内皮生长因子和内皮型一氧化氮合酶的mRNA表达通过Erk 1/2依赖mechanism. Conclusion-这些结果表明，内源性ANP和BNP在缺血组织修复性血管重塑中发挥重要作用。（Arterioscler Thromb Vasc Biol.2009; 29：1516-1521.）
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. (Arterioscler Thromb Vasc Biol. 2009; 29: 1516-1521.)