ROLE OF ANGIOTENSIN-II IN THE REGULATION OF A NOVEL VASCULAR MODULATOR, HEPATOCYTE GROWTH-FACTOR (HGF), IN EXPERIMENTAL HYPERTENSIVE RATS

Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic fac tor that regulates cell growth, cell motility, and morphogenesis of va rious types of cells, and is thus considered a humoral mediator of epi thelial-mesenchymal interactions responsible for morphogenic tissue in teractions. We have previously reported that HGF is a novel member of endothelium-specific growth factors whose serum concentration is posit ively associated with blood pressure in humans. Therefore, we speculat ed that serum HGF secretion might be elevated in response to high bloo d pressure as a counter-system against endothelial dysfunction. Howeve r, it is difficult to elucidate the role of circulating and tissue HGF s in human hypertension. To address this issue, we measured circulatin g and tissue HGF concentrations in spontaneously hypertensive rats (SH R) and Wistar-Kyoto rats (WKY) at different ages. Serum HGF concentrat ion in SHR was significantly higher than that in WKY at 6, 15, and 25 weeks of age (P<.01). Serum HGF concentration was also significantly p ositively correlated with blood pressure in SHR (P<.02, r=.455). In co ntrast, tissue HGF concentrations in heart, aorta, and kidney were sig nificantly decreased in SHR as compared with WKY at 25 weeks of age, w hen these organs showed hypertrophic changes induced by hypertension ( P<.01). Cardiac HGF mRNA was also decreased in SHR as compared with WK Y at 25 weeks of age. Moreover, cardiac HGF concentration showed a sig nificant negative correlation with left ventricular (LV) weight (P<.01 ), whereas serum HGF concentration showed a significant positive corre lation with LV weight (P<.05). Interestingly, concentrations of cardia c and vascular angiotensin II, a suppressor of HGF, were increased in SHR as compared with WKY at 25 weeks of age (P<.01). Therefore, we exa mined the effects of angiotensin blockade on circulating and tissue HG F concentrations, to study the role of angiotensin II in HGF regulatio n. Administration of an angiotensin-converting enzyme inhibitor (enala pril) and angiotensin II type 1 receptor antagonists (losartan and HR 720) for 6 weeks resulted in a significant increase in cardiac HGF con centration, accompanied by increased cardiac HGF mRNA, and a significa nt decrease in serum HGF concentration, accompanied by lowered blood p ressure and reduced LV weight (P<.01). Here, we demonstrated increased circulating HGF and decreased vascular, cardiac, and renal HGF in SHR as compared with WKY at the maintenance stage of hypertension. Decrea sed tissue HGF in target organs of hypertension may be due to increase d tissue angiotensin II. These results suggest that decreased local HG F production may have an important role in the cardiovascular remodeli ng of target organs in hypertension, since HGF prevented endothelial i njury and promoted angiogenesis. Blockade of angiotensin augmented loc al decreased cardiovascular HGF in hypertension, potentially resulting in the improvement of endothelial dysfunction.