Exp Mol Med.  2001 Jun;33(2):95-102.

Potential role of leptin in angiogenesis: leptin induces endothelial cell proliferation and expression of matrix metalloproteinases in vivo and in vitro

• Park HY
• Kwon HM
• Lim HJ
• Hong BK
• Lee JY
• Park BE
• Jang YS
• Cho SY
• Kim HS

Abstract

Leptin, the product of ob gene, is an endocrine hormone that regulates adipose tissue mass. Recently, leptin has been found to generate a growth signal involving a tyrosine kinase-dependent intracellular pathway and promote angiogenic processes via activation of leptin receptor (Ob-R) in endothelial cells. However, it is not clear how leptin functions to promote multi-step processes involved in the neovascularization at the atherosclerotic plaque. We have examined the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) and Ob-R in human atherosclerotic lesions, leptin-mediated angiogenesis in vivo and in vitro. Immunohistochemical analysis of human atherosclerotic aorta revealed an increased expression of Ob-R in the intima of neorevascularized regions and of both MMPs and TIMPs predominantly in the endothelial lining of intimal neovessels and macrophages/foam cells. In the rat corneal angiogenesis assay, leptin elicited a comparable sensitivity of angiogenic activity to those of vascular endothelial growth factor (VEGF). The immunohistological analysis of the leptin-treated rat cornea showed definitive rises in Ob-R, MMPs and TIMPs expression as well as those of VEGF receptor (VEGFR-1). Leptin (10-40 ng/ml) induced proliferation of the human umbilical vein endothelial cells (HUVECs) and elevation of MMP-2, MMP-9, TIMP-1, and TIMP-2 expression in a dose-dependent manner. Leptin also induced increases of MMP-2, MMP-9, TIMP-1, and Up-regulated the human coronary artery smooth muscle cells (HCASMCs). These findings suggest that leptin, a hormone with pluralistic properties including a mitogenic activity on vascular endothelial cells, plays a role in matrix remodeling by regulating the expression of MMPs and TIMPs. Taken together, our findings further provide evidences for leptin's role as an angiogenesis inducer in the normal organ (rat cornea) and in aberrant vasculature under duress like atherosclerosis.

Keyword

leptin; angiogenesis; MMPs; atherosclerosis

MeSH Terms

Animal
Arteriosclerosis/metabolism
Blotting, Western
Cell Division
Cells, Cultured
Dose-Response Relationship, Drug
Endothelial Growth Factors/metabolism
Endothelium, Vascular/*cytology/*enzymology
Enzyme-Linked Immunosorbent Assay
Fibroblast Growth Factor 2/metabolism
Immunohistochemistry
Leptin/*chemistry/metabolism/*physiology
Lymphokines/metabolism
Matrix Metalloproteinases/*biosynthesis
*Neovascularization, Pathologic
Rats
Receptor Protein-Tyrosine Kinases/metabolism
Receptors, Growth Factor/metabolism
Recombinant Proteins/metabolism
Support, Non-U.S. Gov't
Tissue Inhibitor of Metalloproteinases/metabolism
Umbilical Veins/metabolism
Up-Regulation