Natriuretic Peptides Attenuate Retinal Pathological Neovascularization Via Cyclic GMP Signaling in Pericytes and Astrocytes.

Spes, Katarina Špiranec; Hupp, Sabrina; Werner, Franziska; Koch, Franziska; Völker, Katharina; Krebes, Lisa; Kämmerer, Ulrike; Heinze, Katrin G; Braunger, Barbara M; Kuhn, Michaela (2020). Natriuretic Peptides Attenuate Retinal Pathological Neovascularization Via Cyclic GMP Signaling in Pericytes and Astrocytes. Arteriosclerosis, thrombosis, and vascular biology, 40(1), pp. 159-174. Lippincott Williams & Wilkins 10.1161/ATVBAHA.119.313400

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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-Cre ERT2 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy

UniBE Contributor:

Hupp, Sabrina

Subjects:

500 Science
600 Technology > 610 Medicine & health

ISSN:

1079-5642

Publisher:

Lippincott Williams & Wilkins

Language:

English

Submitter:

Sabrina Hupp

Date Deposited:

25 Oct 2019 15:56

Last Modified:

25 Dec 2019 01:31

Publisher DOI:

10.1161/ATVBAHA.119.313400

PubMed ID:

31619060

Uncontrolled Keywords:

apoptosis astrocyte mice oxygen pericyte

BORIS DOI:

10.7892/boris.134268

URI:

https://boris.unibe.ch/id/eprint/134268

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