Examining the Actions of Insulin-Like Growth Factor Binding Protein 2 in Vascular Biology

The formation of new blood vessels; physiological function of quiescent vasculature; and remodelling of vasculature after injury, is regulated by a wide variety of complex and overlapping signalling pathways. The endothelial cell monolayer, vascular smooth muscle cells and adventitial tissue which constitute blood vessels are influenced by multiple circulating and locally secreted factors, with each tissue type exerting effects on the other; especially in the context of angiogenesis and in the pathophysiological response to vascular injury. Insulin-like growth factor binding protein-2 (IGFBP-2) has been considered an important factor in tumour angiogenesis and cellular proliferation, but little is known about its effects on vascular function, vascular remodelling, and its effects on the individual cell types within the vascular environment. In this work, we describe the effects of IGFBP-2 on vascular physiological and pathophysiological processes. We achieved this predominantly through the use of two transgenic murine models: of conditional endothelial specific IGFBP-2 overexpression, and conditional global IGFBP-2 overexpression. We demonstrate that endothelial specific IGFBP-2 overexpression has no effect on ex vivo aortic vasomotor function, whilst global overexpression of IGFBP-2 causes significant aortic hypocontractility, but without any change in endothelium-dependent vasodilatation, and without altering nitric oxide bioavailability. No change for in vivo blood pressure was evident, with increased aortic distensibility seen with global overexpression of IGFBP-2. We also demonstrate that global overexpression of IGFBP-2 leads to reduced re-endothelialization after vascular injury, but does not affect neointimal quantity, although possible changes in neointima composition were observed. Finally, increased exposure to IGFBP-2 caused an increase in sprouting angiogenesis across multiple endothelial cell types. In conclusion, increased expression of IGFBP-2 may exert multiple effects on murine vasculature in the setting of vascular vasomotor function, vascular injury and angiogenesis. More work is required to further understand the effects IGFBP-2 exerts in vascular biology, and the signalling mechanisms through which these occur.