Natriuretic Peptides Attenuate Retinal Pathological Neovascularization Via Cyclic GMP Signaling in Pericytes and Astrocytes.
Natriuretic Peptides Attenuate Retinal Pathological Neovascularization Via Cyclic GMP Signaling in Pericytes and Astrocytes.
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DOI：
10.1161/atvbaha.119.313400
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发表时间：
2019-04
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影响因子：
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通讯作者：
Katarina Špiranec Spes;Sabrina Hupp;F. Werner;F. Koch;K. Völker;Lisa Krebes;U. Kämmerer;K. Heinze;B. Braunger;M. Kuhn
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作者：
Katarina Špiranec Spes;Sabrina Hupp;F. Werner;F. Koch;K. Völker;Lisa Krebes;U. Kämmerer;K. Heinze;B. Braunger;M. Kuhn
目的：在增殖性视网膜病变中，由新生血管形成引起的并发症可导致失明。在疾病早期，周细胞凋亡导致内皮功能障碍和渗漏。然后缺氧驱动VEGF（血管内皮生长因子）分泌和病理性新生血管生成。心脏ANP（心房利钠肽）有助于系统微循环稳态。ANP也在视网膜中形成，但功能不明确。在这里，我们表征了内源性形成的ANP是否调节视网膜（新）血管生成。方法与结果：研究了cgmp形成ANP受体GC-A （guanyyl cyclase-A）缺失小鼠视网膜血管发育和缺血驱动的新生血管。将带有固定GC-A基因的小鼠与Tie2-Cre、GFAP-Cre或pdgf - r - β- creert2系杂交，在体内解剖ANP在内皮细胞、星形胶质细胞和周细胞介导的作用。在全球GC-A缺失（KO）的新生儿中，血管发育轻度延迟。此外，这些KO小鼠在氧诱导视网膜病变模型中表现出血管消退增强和缺血驱动的新血管形成加剧。值得注意的是，内皮细胞中GC-A的缺失并不影响视网膜血管的发育或病理性新生血管。体外ANP/GC-A/cGMP信号通路通过激活cGMP依赖性蛋白激酶I，抑制缺氧驱动的星形胶质细胞VEGF分泌和TGF-β诱导的周细胞凋亡。在星形胶质细胞中缺乏ANP/GC-A信号的新生儿中，血管发育和高氧驱动的血管退化没有改变；缺血诱导的新生血管略有增加。值得注意的是，在氧诱导的视网膜病变中，周细胞中GC-A的失活延缓了视网膜生理性血管形成，并显著增强了细胞凋亡、血管退化和随后的新生血管形成。结论ANP/GC-A/cGMP通路对实验性增殖性视网膜病变的发生和发展具有保护周细胞的作用。我们的观察表明，内源性周细胞ANP信号的增强是治疗与新生血管相关的视网膜病变的靶点。
OBJECTIVE In proliferative retinopathies, complications derived from neovascularization cause blindness. During early disease, pericyte's apoptosis contributes to endothelial dysfunction and leakage. Hypoxia then drives VEGF (vascular endothelial growth factor) secretion and pathological neoangiogenesis. Cardiac ANP (atrial natriuretic peptide) contributes to systemic microcirculatory homeostasis. ANP is also formed in the retina, with unclear functions. Here, we characterized whether endogenously formed ANP regulates retinal (neo)angiogenesis. Approach and Results: Retinal vascular development and ischemia-driven neovascularization were studied in mice with global deletion of GC-A (guanylyl cyclase-A), the cGMP-forming ANP receptor. Mice with a floxed GC-A gene were interbred with Tie2-Cre, GFAP-Cre, or PDGF-Rβ-CreERT2 lines to dissect the endothelial, astrocyte versus pericyte-mediated actions of ANP in vivo. In neonates with global GC-A deletion (KO), vascular development was mildly delayed. Moreover, such KO mice showed augmented vascular regression and exacerbated ischemia-driven neovascularization in the model of oxygen-induced retinopathy. Notably, absence of GC-A in endothelial cells did not impact retinal vascular development or pathological neovascularization. In vitro ANP/GC-A/cGMP signaling, via activation of cGMP-dependent protein kinase I, inhibited hypoxia-driven astrocyte's VEGF secretion and TGF-β-induced pericyte apoptosis. In neonates lacking ANP/GC-A signaling in astrocytes, vascular development and hyperoxia-driven vascular regression were unaltered; ischemia-induced neovascularization was modestly increased. Remarkably, inactivation of GC-A in pericytes retarded physiological retinal vascularization and markedly enhanced cell apoptosis, vascular regression, and subsequent neovascularization in oxygen-induced retinopathy. CONCLUSIONS Protective pericyte effects of the ANP/GC-A/cGMP pathway counterregulate the initiation and progression of experimental proliferative retinopathy. Our observations indicate augmentation of endogenous pericyte ANP signaling as target for treatment of retinopathies associated with neovascularization.