Physiological roles and therapeutic implications of hepatocyte growth factor for angiogenesis

Abstract

Angiogenesis is an important event for organ development and regeneration via supply of nutrition and oxygen. Appropriate cellular responses, such as endothelial cell (EC) growth, are involved in the angiogenic actions, especially under hypoxic conditions. Hepatocyte growth factor (HGF) is now an organotrophic factor that is essential for organ development and tissue regeneration. In addition, HGF is the most potent angiogenic growth factor in culture of ECs, with mitogenic, and morphogenic functions via activation of c-Met/HGF-receptor. In hypoxic diseases, such as coronary arterial disease (CAD), up-regulation of HGF production is transient, followed by the HGF-deficient conditions, along with the lowered angiogenesis and enhanced hypoxia. Enhancement of angiogenesis by exogenous HGF leads to the improvement in heart dysfunction. Such angio-therapeutic effects of HGF are also seen in various hypoxic diseases, such as skin ulcer and lung emphysema. In tumor tissues, angiogenesis is required for cancer growth and metastasis. Indeed, an HGF-antagonist, NK4, potently inhibits tumor angiogenesis and metastasis in mouse models of malignant tumors. These provide a rationale why HGF is useful for the improvement in CAD and other ischemic diseases and NK4 for the suppression of tumor malignancy. Importantly, appropriate HGF-c-Met signal is required for sustaining homeostasis in normal tissue. Herein, we provide a concept that amount of HGF may determine the predisposition to ischemic disease, healthy conditions, or neoplastic disease, all of which depend on the degree of c-Met activation, and in part, concomitant angiogenic activity.