Park H Y, Kwon H M, Lim H J, Hong B K, Lee J Y, Park B E, Jang Y, Cho S Y, Kim H S
Yonsei Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Korea.
Exp Mol Med. 2001 Jun 30;33(2):95-102. doi: 10.1038/emm.2001.17.
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.
瘦素是肥胖（ob）基因的产物，是一种调节脂肪组织量的内分泌激素。最近，人们发现瘦素可产生一种涉及酪氨酸激酶依赖性细胞内途径的生长信号，并通过激活内皮细胞中的瘦素受体（Ob-R）促进血管生成过程。然而，尚不清楚瘦素如何发挥作用以促进动脉粥样硬化斑块处新血管形成所涉及的多步骤过程。我们研究了基质金属蛋白酶（MMPs）、金属蛋白酶组织抑制剂（TIMPs）和Ob-R在人类动脉粥样硬化病变中的表达，以及瘦素在体内和体外介导的血管生成。对人类动脉粥样硬化主动脉的免疫组织化学分析显示，在新血管形成区域的内膜中Ob-R表达增加，而MMPs和TIMPs主要在内膜新血管的内皮衬里以及巨噬细胞/泡沫细胞中表达增加。在大鼠角膜血管生成试验中，瘦素引发的血管生成活性敏感性与血管内皮生长因子（VEGF）相当。对瘦素处理的大鼠角膜进行免疫组织学分析显示，Ob-R、MMPs、TIMPs以及VEGF受体（VEGFR-1）的表达均有明显升高。瘦素（10 - 40 ng/ml）以剂量依赖性方式诱导人脐静脉内皮细胞（HUVECs）增殖，并使MMP-2、MMP-9、TIMP-1和TIMP-2的表达升高。瘦素还诱导MMP-2、MMP-9、TIMP-1增加，并上调人冠状动脉平滑肌细胞（HCASMCs）。这些发现表明，瘦素作为一种对血管内皮细胞具有促有丝分裂活性等多种特性的激素，通过调节MMPs和TIMPs的表达在基质重塑中发挥作用。综上所述，我们的研究结果进一步证明了瘦素在正常器官（大鼠角膜）以及在动脉粥样硬化等应激状态下异常脉管系统中作为血管生成诱导剂的作用。
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