Altered insulin-like growth factor-1 and nitric oxide sensitivities in hypertension contribute to vascular hyperplasia |
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| Institution: | 1. Department of Physiology, Midwestern University, Glendale, Arizona, USA;1. University of Arkansas for Medical Sciences (UAMS) and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA;1. Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan;1. Department of Pharmacology, University of Uppsala, Uppsala Sweden;2. Department of Psychiatry, Karolinska Institute, St. Göran''s Hospital, Stockholm Sweden;1. Institute of Physiology (KM, IM, JK, JP), Czech Academy of Sciences, Prague Czech Republic;2. Second Faculty of Medicine (KM), Charles University, Prague Czech Republic;2. Department of Experimental Medicine and Oncology, General Pathology Section, University of Torino, Torino, Italy;1. Department of Neurological Sciences and Vision, University of Genova, Genova, Italy;1. Hypertension Unit, Clinica Medica, Department of Experimental and Clinical Pathology and Medicine, University of Udine (CC, MN, GC, AC, LAS), Udine, Italy;2. Clinica di Endocrinologia, University of Ancona (GG), Ancona, Italy |
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| Abstract: | Vascular medial thickening, a hallmark of hypertension, is associated with vascular smooth muscle cell (VSMC) hypertrophy and hyperplasia. Although the precise mechanisms responsible are elusive, we have shown that strain induced regulation of autocrine insulin-like growth factor-1 (IGF-1) and nitric oxide (NO) reciprocally modulate VSMC proliferation. Therefore, we investigated potential IGF-1 and NO abnormalities in young (10-week-old) spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) and their respective VSMC ex vivo. The SHR had increased mean arterial pressure (173 ± 2 v 128 ± 3 mm Hg, n = 24, P < .05) but similar pulse pressures (31 ± 2 v 30 ± 3 mm Hg; P > .05) v WKY. The SHR exhibited increased aortic wall thickness in comparison with WKY (523 ± 16 v 355 ± 17μm; P < .05). No differences were seen in plasma combined NO2 and NO3 (NOx) (0.48 ± 0.11 mmol/L for WKY v 0.58 ± 0.18 mmol/L for SHR) or plasma IGF-1 (1007 ± 28 ng/mL for WKY v 953 ± 26 ng/mL for SHR). Aortic VSMC from SHR displayed enhanced proliferation in comparison with WKY (P < .05). Underlying this enhanced proliferation was altered SHR VSMC sensitivity to the antiproliferative NO donor 2,2"Hydroxynitrosohydrazono] bis-ethanimine (DETA-NO) (ID50: 270 ± 20 mmol/L for SHR; 150 ± 11 mmol/L for WKY; P < .05). Basal cyclic guanosine monophosphate (cGMP) secretion from SHR VSMC was 65-fold greater than that seen from WKY (P < .001). In response to DETA-NO, cGMP secretion from SHR VSMC increased modestly (1.5-fold; P < .01), whereas treatment of WKY VSMC resulted in a 26-fold (P < .001) increase in cGMP. The SHR VSMC did not respond to exogenous IGF-1, whereas WKY VSMC exhibited a dose dependent increase in proliferation with IGF-1 (10−10 to 10−7 mol/L). These data suggest that VSMC hyperplasia in early hypertension is not reflected by imbalances in plasma IGF-1 or NO. Rather, altered SHR VSMC sensitivity to NO is likely responsible in part for the observed hyperproliferation seen in early stages of hypertension. |
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