Significance and therapeutic potential of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway in vascular regeneration
Significance and therapeutic potential of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway in vascular regeneration
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DOI：
10.1073/pnas.0538059100
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发表时间：
2003-03-18
影响因子：
11.1
通讯作者：
Nakao, K
中科院分区：
文献类型：
--
作者：
Yamahara, K;Itoh, H;Nakao, K
利钠肽(NPs)由心房型、脑型和C型利钠肽(分别为ANP、BNP和CNP)组成，是一种心脏或血管激素，通过激活cGMP/cGMP依赖的蛋白激酶(CGK)途径而产生生物学效应。我们最近报道了将CNP基因转移到兔血管中，不仅抑制了新生内膜的形成，而且加速了血管内皮化，这是内皮依赖的血管松弛和抗血栓形成所必需的步骤。因此，我们研究了NPs/cGMP/CGK通路在血管再生中的治疗潜力。在后肢缺血后高表达BNP的转基因(TG)小鼠中，适当的壁细胞涂层加速了新生血管的形成，而没有水肿或出血，并有效地挽救了因抑制一氧化氮产生而受损的血管生成。此外，与对照组相比，BNP-TG组小鼠缺血组织中的炎性细胞浸润和血管超氧化物生成受到抑制。缺血诱导的血管生成在CGK I型转基因小鼠中也显著增强，但在CGK I型基因敲除小鼠中减弱。NPS通过刺激CGK和随后的ERK1/2激活，显著刺激培养的内皮细胞形成毛细血管网络。此外，将CNP基因转移到缺血肌中可有效促进血管生成。这些发现揭示了NPs/cGMP/CGK通路在没有明显不良反应的情况下发挥多种血管保护和再生作用，因此提示NPs作为内源性心血管激素可以作为组织缺血患者治疗性血管生成的策略。
Natriuretic peptides (NPs), which consist of atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP, respectively), are characterized as cardiac or vascular hormones that elicit their biological effects by activation of the cGMP/cGMP-dependent protein kinase (cGK) pathway. We recently reported that adenoviral gene transfer of CNP into rabbit blood vessels not only suppressed neointimal formation but also accelerated reendothelialization, a required step for endothelium-dependent vasorelaxation and antithrombogenicity. Accordingly, we investigated the therapeutic potential of the NPs/cGMP/cGK pathway for vascular regeneration. In transgenic (Tg) mice that overexpress BNP in response to hindlimb ischemia, neovascularization with appropriate mural cell coating was accelerated without edema or bleeding, and impaired angiogenesis by the suppression of nitric oxide production was effectively rescued. Furthermore, in BNP-Tg mice, inflammatory cell infiltration in ischemic tissue and vascular superoxide production were suppressed compared with control mice. Ischemia-induced angiogenesis was also significantly potentiated in cGK type I Tg mice, but attenuated in cGK type I knockout mice. NPs significantly stimulated capillary network formation of cultured endothelial cells by cGK stimulation and subsequent Erk1/2 activation. Furthermore, gene transfer of CNP into ischemic muscles effectively accelerated angiogenesis. These findings reveal an action of the NPs/cGMP/cGK pathway to exert multiple vasculoprotective and regenerative actions in the absence of apparent adverse effects, and therefore suggest that NPs as the endogenous cardiovascular hormone can be used as a strategy of therapeutic angiogenesis in patients with tissue ischemia.