Chordin-like 1, a bone morphogenetic protein-4 antagonist, is upregulated by hypoxia in human retinal pericytes and plays a role in regulating angiogenesis

Abstract

Diabetic retinopathy is a microvascular complication of both Type 1 and Type 2 diabetes and is characterized by increased tissue ischemia, angiogenesis, and permeability. This microvascular disease is a major cause of blindness in the working age population [1]. The development of diabetic retinopathy reflects the convergence of hemodynamic and metabolic insults, including hyperglycemia, in susceptible individuals.

Vascular endothelial growth factor (VEGF) is known to be induced by hypoxia and may mediate hypoxia-induced angiogenesis [2]. VEGF alone is sufficient to produce many of the vascular abnormalities common to diabetic retinopathy and other ischemic retinopathies, such as hemorrhage, edema, venous beading, capillary occlusion with ischemia, microaneurysm formation, and intraretinal vascular proliferation [3].

Retinal pericytes are smooth muscle-like cells with attenuated processes enveloping the abluminal surface of microvessels and sharing a common basement membrane with the underlying endothelium (reviewed in [4]). Pericytes express alpha-smooth muscle actin and have thus been
implicated to have a contractile function [5]. They are proposed to regulate microvascular angiogenesis and synthesize components of the vascular basement membrane [6,7]. Pericytes have been demonstrated to be involved in the regulation of endothelial cell number and morphology and microvessel architecture [8].

In this study we present novel findings that chordin-like 1 (CHL-1), a bone morphogenetic protein (BMP) antagonist [9], is upregulated by hypoxia in human retinal pericytes, and that its expression is driven by hypoxia inducible factor-1α (HIF-1α). CHL-1 has previously been reported to be expressed in the developing retina [9], but has not yet been associated with diabetic or ischemic retinopathy. BMP-4 has been implicated in angiogenesis through a VEGF-dependent mechanism [10]. We therefore propose that CHL-1 expression by human retinal pericytes in response to hypoxia may play an important role in regulating retinal angiogenesis through modulation of BMP-4 actions on endothelial cells.