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 (cyclic guanosine monophosphate)-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 (transforming growth factor beta)-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.

中文翻译：

---

利钠肽通过周环鸟和星形胶质细胞中循环鸟苷单磷酸信号减弱视网膜病理性新血管形成。

目的在增生性视网膜病变中，新血管形成引起的并发症会导致失明。在疾病早期，周细胞的凋亡导致内皮功能障碍和渗漏。缺氧然后驱动VEGF（血管内皮生长因子）分泌和病理性新血管生成。心脏ANP（心钠素）有助于系统性微循环稳态。ANP也形成于视网膜中，功能不清楚。在这里，我们表征是否内源性形成的ANP调节视网膜（新）血管生成。方法和结果：在具有整体缺失GC-A（鸟苷酸环化酶-A），形成cGMP（环状鸟苷一磷酸）的ANP受体的小鼠中研究了视网膜血管的发育和缺血驱动的新血管形成。将带有GC-A基因浮雕的小鼠与Tie2-Cre，GFAP-Cre，或PDGF-Rβ-CreERT2细胞系可在体内解剖内皮，星形胶质细胞与周细胞介导的ANP作用。在具有整体GC-A缺失（KO）的新生儿中，血管发育被轻度延迟。而且，这种KO小鼠在氧诱导性视网膜病模型中显示出增加的血管退化和加剧的缺血驱动的新血管形成。值得注意的是，内皮细胞中不存在GC-A不会影响视网膜血管的发育或病理性新血管形成。体外ANP / GC-A / cGMP信号传导通过激活cGMP依赖性蛋白激酶I抑制缺氧驱动的星形胶质细胞的VEGF分泌和TGF-β（转化生长因子β）诱导的周细胞凋亡。在星形胶质细胞缺乏ANP / GC-A信号的新生儿中，血管发育和高氧驱动的血管消退没有改变。缺血引起的新血管形成适度增加。值得注意的是，周细胞中GC-A的失活会延迟生理性视网膜血管形成，并显着增强细胞凋亡，血管退化和随后的氧诱导性视网膜病变的新血管形成。结论ANP / GC-A / cGMP途径的保护性周细胞作用可调节实验性增生性视网膜病的发生和发展。我们的观察结果表明，内源性周细胞ANP信号的增强可作为治疗与新生血管相关的视网膜病变的靶标。结论ANP / GC-A / cGMP途径的保护性周细胞作用可调节实验性增生性视网膜病的发生和发展。我们的观察结果表明，内源性周细胞ANP信号的增强可作为治疗与新生血管相关的视网膜病变的靶标。结论ANP / GC-A / cGMP途径的保护性周细胞作用可调节实验性增生性视网膜病的发生和发展。我们的观察结果表明，内源性周细胞ANP信号的增强可作为治疗与新生血管相关的视网膜病变的靶标。