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-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 (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.

The role of cGMP signalling in auditory processing in health and disease

“…They are, therefore, also expected to play a role in progressing hearing loss over age or through acoustic trauma. It is moreover interesting in this context that GC‐A deletion in pericytes was shown to lead to retarded physiological retinal vascularization and enhanced cell apoptosis of the retina (Špiranec Spes et al, 2020). Pericytes are suggested to regulate not only blood–brain barrier permeability but also angiogenesis and capillary haemodynamic responses (Sweeney et al, 2016), suggesting that GC‐A in pericytes may play a role in hearing under challenging situations in which proper central memory‐dependent auditory adjustment processes are vital for recovery from noise‐ and age‐dependent hearing loss (Liu et al, 2016; Marchetta, Möhrle, et al, 2020; Matt et al, 2018).…”

The neuroprotection effects of exosome in central nervous system injuries: A new target for therapeutic intervention

“…In addition to upholding normal brain activities, astrocytes can function as reactive astrogliosis following CNS injuries by regulation of gene expression, morphology and proliferative capacity [19]. Reactive astrogliosis are capable of secreting soluble factors such as transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), glial-derived neurotrophic factor (GDNF) and basic broblast growth factor (bFGF), which further activated in ammatory response after CNS injuries [20]. The diversity functions of astrocytes make them predominant among other cells in CNS [21,22].…”

Corin Deficiency Alters Adipose Tissue Phenotype and Impairs Thermogenesis in Mice

“…As part of the cardiac endocrine system, ANP promotes vasodilation in peripheral vessels and natriuresis in the kidney to preserve normal blood volume and pressure. Moreover, ANP acts in the heart to maintain cellular structure and function [ 6 , 7 ] and in non-cardiac tissues to regulate inflammation [ 8 , 9 , 10 ] and vascular remodeling [ 11 , 12 , 13 ]. Polymorphisms in the NPPA gene, encoding the ANP precursor, have been associated with blood pressure levels [ 14 ] and cardiovascular disorders [ 15 , 16 ].…”