Endothelial insulin-like growth factor-1 signaling regulates vascular barrier function and atherogenesis.

Abstract

Aims: Progressive deposition of cholesterol in the arterial wall characterizes atherosclerosis, which underpins most cases of myocardial infarction and stroke. Insulin-like growth factor-1 (IGF-1) is a hormone that regulates systemic growth and metabolism and possesses anti-atherosclerotic properties. We asked whether endothelial-restricted augmentation of IGF-1 signaling is sufficient to suppress atherogenesis.

Methods and results: We generated mice with endothelial-restricted over-expression of human wildtype IGF-1R (hIGFREO/ApoE-/-) or a signaling defective K1003R mutant human IGF-1R (mIGFREO/ApoE-/-) and compared them to their respective ApoE-/- littermates. hIGFREO/ApoE-/- had less atherosclerosis, circulating leukocytes, arterial cholesterol uptake, and vascular leakage in multiple organs, whereas mIGFREO/ApoE-/- did not exhibit these phenomena. Overexpressing wildtype IGF-1R in human umbilical vein endothelial cells (HUVEC) altered the localization of tight junction proteins and reduced paracellular leakage across their monolayers, whilst overexpression of K1003R IGF-1R did not have these effects. Moreover, only overexpression of wildtype IGF-1R reduced HUVEC internalization of cholesterol-rich low density lipoprotein particles and increased their association of these particles with clathrin, but not caveolin-1, implicating it in vesicular uptake of lipoproteins. Endothelial overexpression of wildtype versus K1003R IGF-1R also reduced expression of YAP/TAZ target genes and nuclear localization of TAZ, which may be relevant to its impact on vascular barrier and atherogenesis.

Conclusions: Endothelial IGF-1 signaling modulates both para- and trans-cellular vascular barrier function. Beyond reducing atherosclerosis, this could have relevance to many diseases associated with abnormal vascular permeability.