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

Abstract

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.

• Authors: Katarina Špiranec Spes, Sabrina Hupp, Franziska Werner, Franziska Koch, Katharina Völker, Lisa Krebes, Ulrike Kämmerer, Katrin G Heinze, Barbara M Braunger, Michaela Kuhn
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 40 Issue 1 Pg. 159-174 (01 2020) ISSN: 1524-4636 [Electronic] United States
• PMID: 31619060 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Natriuretic Peptides
• RNA
• Cyclic GMP

Topics

• Animals
• Animals, Newborn
• Apoptosis
• Astrocytes (metabolism, pathology)
• Cells, Cultured
• Cyclic GMP (biosynthesis, genetics)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Gene Expression Regulation, Developmental
• Immunoblotting
• Mice
• Mice, Transgenic
• Natriuretic Peptides (metabolism)
• Pericytes (metabolism, pathology)
• RNA (genetics)
• Retinal Neovascularization (genetics, metabolism, pathology)
• Signal Transduction