Hepatocyte growth factor is a survival factor for endothelial cells and is expressed in human atherosclerotic plaques Harry Ma a , Tina M. Calderon a , John T. Fallon b , Joan W. Berman c, * a Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA b Departments of Pathology and Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA c Departments of Pathology and Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA Received 1 October 2001; received in revised form 18 January 2002; accepted 12 February 2002 Abstract Hepatocyte growth factor (HGF) has multiple effects on target cells upon activation of its receptor, c-Met. In endothelial cells, HGF induces migration, proliferation, and angiogenesis. HGF can also act as an anti-apoptotic factor for several cell types. The signal transduction pathways involved in mediating its anti-apoptotic effects have not been fully clarified. We demonstrated that HGF is anti-apoptotic for human endothelial cells, and identified the signaling pathways by which it mediates its effects. Human umbilical vein endothelial cells (HUVEC) exhibited significant levels of apoptosis after serum deprivation. HGF inhibited apoptosis in a dose dependent manner in serum-deprived cultures. HGF induced the phosphorylation of Akt and Erk1/2, cell survival factors, in a time dependent manner in serum deprived HUVEC. Inhibition of Akt and Erk1/2 activation abolished the anti-apoptotic effects of HGF. The transcription factor, NF-kB, can also play a role in promoting cell survival. However, NF-kB does not appear to contribute to the anti-apoptotic properties of HGF, as nuclear translocation of NF-kB was not detected in HGF-treated cultures. Endothelial cell migration, proliferation, and apoptosis contribute to the pathogenesis of atherosclerosis, and HGF may play a role in the development and progression of vascular lesions. Immunohistochemical analysis of human carotid artery sections demonstrated HGF protein localization within atherosclerotic lesions but not in normal vessels, suggesting that HGF may participate in atherogenesis. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Apoptosis; Atherosclerosis; Endothelium; Hepatocyte growth factor 1. Introduction Hepatocyte growth factor (HGF) is a mesenchymal- derived protein that regulates cell growth, cell motility, and morphogenesis of various cell types, including endothelial cells [1,2]. Recent studies demonstrated that HGF is a potent angiogenic factor that can induce endothelial cell proliferation and migration, without induction of vascular smooth muscle cell (VSMC) division [3]. In addition, HGF can act as a survival factor for endothelial cells [4]. Understanding how HGF can inhibit endothelial cell apoptosis has important implications for the mainte- nance of endothelial cell function. Alterations of HGF levels in vascular disorders that involve endothelial cell injury or apoptosis would suggest that HGF plays a significant role in pathological processes. Others have shown that patients with hypertension have increased serum levels of HGF, while patients with arterial occlusive disease have decreased serum levels of HGF [5]. In addition, recombinant HGF-induced angiogen- esis can attenuate the tissue damage and cell death associated with ischemic injury [6]. Endothelial cell injury is a critical event that can act as the initial trigger in vascular diseases such as athero- sclerosis. The deposition of low-density lipoproteins (LDL) within the vessel wall is thought to be one of the early insults that initiates an inflammatory response. Lesions then progress due to recruitment of inflamma- tory cells, migration and proliferation of VSMC, and formation of a lipid core within the intima of the vessel * Corresponding author. Tel.: 1-718-430-3194; fax: 1-718-430- 8541. E-mail address: berman@aecom.yu.edu (J.W. Berman). Atherosclerosis 164 (2002) 79  /87 www.elsevier.com/locate/atherosclerosis 0021-9150/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII:S0021-9150(02)00062-X