Secretogranin III: a diabetic retinopathy-selective angiogenic factor

Abstract

Secretogranin III (Scg3) is a member of the granin protein family that regulates the biogenesis of secretory granules. Scg3 was recently discovered as an angiogenic factor, expanding its functional role to extrinsic regulation. Unlike many other known angiogenic factors, the pro-angiogenic actions of Scg3 are restricted to pathological conditions. Among thousands of quantified endothelial ligands, Scg3 has the highest binding activity ratio to diabetic vs. healthy mouse retinas and lowest background binding to normal vessels. In contrast, vascular endothelial growth factor binds to and stimulates angiogenesis of both diabetic and control vasculature. Consistent with its role in pathological angiogenesis, Scg3-neutralizing antibodies alleviate retinal vascular leakage in mouse models of diabetic retinopathy and retinal neovascularization in oxygen-induced retinopathy mice. This review summarizes our current knowledge of Scg3 as a regulatory protein of secretory granules, highlights its new role as a highly disease-selective angiogenic factor, and envisions Scg3 inhibitors as "selective angiogenesis blockers" for targeted therapy.

Expression Pattern of the LacZ Reporter in Secretogranin III Gene-trapped Mice

“…30 SgIII was expressed in the retina, where it acted as an angiogenic factor in diabetic retinopathy. 31,32 Furthermore, SgIII has been suggested to be involved in signal transduction in neurotoxin-induced apoptosis in dopaminergic neuroblasts. 33 Although the pathophysiological significance of the astrocytic SgIII expression is not fully understood, this protein might be involved in the secretory function of astrocytes (recently also called gliocrine).…”

Spatiotemporal Regulation of Tumor Angiogenesis by Circulating Chromogranin A Cleavage and Neuropilin-1 Engagement

“…A growing body of evidence suggests that granin-derived polypeptides, a family of neurosecretory proteins released in circulation, may significantly contribute to the regulation of vascular biology (4)(5)(6). Among these proteins, chromogranin A (CgA) is emerging as a peculiar vasoregulatory player (5).…”

Secretogranin III promotes angiogenesis through MEK/ERK signaling pathway

“…Scg3 belongs to the granin family, which is composed of chromogranin A (CgA), CgB, and secretogranin II–VIII (Scg2–8) [12]. Granins regulate a broad spectrum of biological activities, including secretion, metabolism, vascular homeostasis, blood pressure, cardiac function, cell adhesion and migration, and innate immunity [13–15].…”

“…Granins regulate a broad spectrum of biological activities, including secretion, metabolism, vascular homeostasis, blood pressure, cardiac function, cell adhesion and migration, and innate immunity [13–15]. Predominantly expressed in endocrine, neuroendocrine and neuronal cells [12], Scg3 was initially discovered as an intravesicular protein that regulates the biogenesis of secretory granules [16]. However, deletion of the Scg3 gene in mice results in a normal phenotype with minimal effects on the secretion of many important hormones, such as insulin and growth hormone [17].…”

“…Scg3 was recently discovered as a novel angiogenesis growth factor in a mouse model of DR using an innovative technology of comparative ligandomics [5]. In the granin family, CgA-derived catestain and Scg2-derived secretoneurin were reported with angiogenic activity, whereas full-length CgA and its cleaved peptide catestain are potent angiogenesis inhibitors [12, 14, 18]. Given that Scg3 shares minimal amino acid sequence homology with its family members, Scg3 and other granins may regulate angiogenesis through different receptors and pathways [12].…”