A Vascular Modulator, Hepatocyte Growth Factor, Is Associated With Systolic Pressure

Abstract

Endothelial cells are known to secrete various antiproliferative and vasodilating factors, such as nitric oxide and natriuretic peptides. The presence of endothelial dysfunction, well known in hypertensive individuals, potentially results in the development and progression of atherosclerosis. Therefore, it is important to know the factors that might influence endothelial cell growth. We examined the mitogenic actions of hepatocyte growth factor (HGF) on human endothelial and vascular smooth muscle cells. Exogenously added human recombinant HGF stimulated endothelial but not vascular smooth muscle cell growth in a dose-dependent manner. We also compared the mitogenic action of HGF with that of basic fibroblast growth factor and vascular endothelial growth factor. Interestingly, the mitogenic action of HGF on endothelial cells was greater than the actions of basic fibroblast growth factor and vascular endothelial growth factor, whereas basic fibroblast growth factor but not HGF and vascular endothelial growth factor stimulated vascular smooth muscle cell growth. Given the characteristics of HGF as an endothelium-specific growth factor, we evaluated the relationship of circulating HGF and blood pressure in normotensive and hypertensive subjects. Serum HGF concentration has been reported to be elevated in response to organ damage, such as in hepatitis and nephritis, and recent findings show that HGF may play an important role in tissue regeneration. We hypothesized that HGF might contribute to the protection or repair of vascular endothelial cells. If so, serum HGF level might be elevated in response to endothelial cell damage induced by hypertension. To test this hypothesis, we measured serum levels of HGF, lipoprotein(a), plasminogen activator inhibitor-1, tissue plasminogen activator, total cholesterol, and blood pressure in 41 normotensive and hypertensive subjects without liver, kidney, or lung damage. Serum HGF concentration was significantly correlated with systolic pressure (P < .01, r = .43) but not diastolic pressure. Serum HGF concentration in hypertensive subjects was significantly higher than in normotensive subjects. None of the other factors showed any correlation with blood pressure. We have demonstrated that HGF is an endothelium-specific growth factor whose serum concentration is significantly associated with systolic pressure. These results suggest that HGF secretion might be elevated in response to high blood pressure as a counterregulatory system against endothelial dysfunction.

Inhibition of Neointima by Angiotensin-Converting Enzyme Inhibitor in Porcine Coronary Artery Balloon-Injury Model

“…As was expected, administration of perindopril significantly increased local HGF expression associated with the inhibition of neointimal formation. Because HGF is an endotheliumspecific growth factor and thus stimulated growth of endothelial cells, 3,4 increased local HGF production would probably stimulate regeneration of endothelial cells after balloon injury. Of particular interest, vasodilator response of ballooninjured coronary arteries was restored by treatment with perindopril versus vehicle.…”

“…Given the importance of endothelial cells, we hypothesize that rapid regeneration of endothelial cells, not accompanied by growth of vascular smooth muscle cells (VSMC), may have therapeutic potential in abnormal vascular growth, such as neointimal formation after angioplasty. From this viewpoint, we previously reported that hepatocyte growth factor (HGF) has the unique characteristic of stimulating endothelial cell growth exclusively without stimulating VSMC growth, 3,4 although HGF is well known to be a mesenchyme-derived pleiotropic factor that regulates cell growth and motility and morphogenesis of various types of cells. 5,6 Moreover, the presence of HGF and its specific receptor, c-met, has been detected in vascular tissues.…”

Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models: preclinical study for treatment of peripheral arterial disease

“…7,8 From this viewpoint, hepatocyte growth factor (HGF) originally cloned as hepatocyte mitogen, 9 is also of particular interest, as HGF exclusively stimulated the growth of endothelial cells without replication of vascular smooth muscle cells (VSMC). [10][11][12] Indeed, we and others previously reported that HGF is a potent angiogenic growth factor which is useful for effective therapeutic angiogenesis in a rabbit ischemia model. 13,14 Unexpectedly, the mitogenic activity of HGF is more potent than that of VEGF in human aortic endothelial cells in vitro, as well as a rabbit hindlimb ischemia model in vivo.…”

Angiogenesis induced by hepatocyte growth factor in non-infarcted myocardium and infarcted myocardium: up-regulation of essential transcription factor for angiogenesis, ets

“…The concentration of HGF in the myocardium was determined by the enzyme-immunoassay with an anti-human HGF antibody, as described previously. 11,15 Briefly, a rabbit anti-rat or an anti-human HGF IgG was coated on 96-well plates (Corning, NY, USA) at 4°C for 15 h. After blocking with 3% bovine serum albumin in phosphate-buffered saline (PBS), the conditioned medium was added to each well. Afterwards, the preparation was incubated for 2 h at 25°C.…”

“…Also HGF is considered a humoral mediator of epithelial-mesenchymal interactions respon-sible for morphogenic tissue interactions during the period of embryonic development and organogenesis. 8,9 Recently, HGF has been reported as a mitogen exclusively for endothelial cells without the replication of vascular smooth muscle cells (VSMC), [10][11][12][13] thereby indicating it as a potential angiogenic growth factor. Indeed, activation of the HGF system promoted angiogenesis in a Matrigel system, 14 however, this system provides far from physiological conditions.…”