Hepatocyte Growth Factor Fusion Protein Having Collagen-Binding Activity (CBD-HGF) Accelerates Re-endothelialization and Intimal Hyperplasia in Balloon-injured Rat Carotid Artery

Abstract

Aim: Hepatocyte growth factor (HGF) is known to stimulate endothelial cell proliferation. However, re-endothelialization is not enhanced when the native protein is administered to the injured artery, probably due to the short half-life of HGF at the site of injury. Therefore, the effects of an HGF fusion protein having collagen-binding activity (CBD-HGF) on re-endothelialization and neointimal formation was studied in the balloon-injured rat carotid artery. Methods: The left common carotid artery of male Sprague-Dawley rats was injured with an inflated balloon catheter, and then treated with CBD-HGF (10 g/mL), HGF (10 g/mL) or saline (control) for 15 min. After 14 days, the rats were injected with Evans blue and sacrificed. Results: The re-endothelialized area was significantly greater in the CBD-HGF-treated rats than in the control or HGF -treated rats. Neointimal formation was significantly more pronounced in the CBD-HGF treated rats than in other rat groups. Both HGF and CBD-HGF stimulated proliferation of vascular smooth muscle cells as well as endothelial cells in vitro. Consistent with this, cultured smooth muscle cells were shown to express the HGF receptor (c-Met). Conclusion: CBD-HGF accelerates re-endothelialization and neointimal formation in vivo. CBD fusion protein is a useful vehicle to deliver vascular growth factors to injured arteries.

Design and Use of Chimeric Proteins Containing a Collagen-Binding Domain for Wound Healing and Bone Regeneration

“…Similarly, intimal hyperplasia can arise when using HGF(129), whereas VEGF is prone to cause hypotension and edema, see heart failure(130).Given their biology, the use of recombinant CBD-growth factor fusions may trigger similar sideeffects. Nonetheless, their binding to collagen fibers hinders both their diffusion and degradation, thus allowing for higher local concentrations, lower systemic distribution and prolonged activity than their native counterparts.…”

Engineering and application of collagen-binding fibroblast growth factor 2 for sustained release

“…For instance, CBD‐EGF has displayed higher proliferation activity and binding activity than the native EGF. Similarly, CBD‐HGF enhanced re‐endothelialization and neointimal formation in vivo . Notably, these beneficial effects have been reported in combination with collagen.…”

VEGF-A/HGF induce Prox-1 expression in the chick embryo chorioallantoic membrane lymphatic vasculature

“…Gerristein [19] emphasized the synergistic effect between VEGF-A and HGF, suggesting a more rapid maturation of neovasculature induced by VEGF-A/HGF, favored by the direct interaction between HGF and its receptor c/met and vascular smooth muscle cells [20][21][22]. If the angiogenic effect of VEGF-A/HGF in combination is widely accepted, their involvement in promotion of lymphangiogenesis is less investigated.…”