TY - JOUR
T1 - Mechanical stretch potentiates angiotensin II-induced proliferation in spontaneously hypertensive rat vascular smooth muscle cells
AU - Liu, Gang
AU - Hitomi, Hirofumi
AU - Hosomi, Naohisa
AU - Lei, Bai
AU - Pelisch, Nicolas
AU - Nakano, Daisuke
AU - Kiyomoto, Hideyasu
AU - Ma, Hong
AU - Nishiyama, Akira
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2010/12
Y1 - 2010/12
N2 - Angiotensin II (AngII) stimulates vascular smooth muscle cell (VSMC) proliferation; however, the effect of AngII on cell proliferation in the presence of mechanical force is not clear. We investigated the mechanism of AngII-induced cell proliferation mediated by mechanical stretch in VSMCs of both normotensive and hypertensive rats. VSMCs obtained from the thoracic aortas of 8-week-old Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were stretched by a Flex culture system. Mechanical stretch significantly upregulated protein expression of AngII type 1 (AT 1) receptor, epidermal growth factor (EGF) receptor and mitogen-activated protein kinase phosphatase-1 in both SHR and WKY VSMCs; however, there was no significant difference in these changes between the cells from SHR and WKY. Mechanical stretch attenuated AngII-induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, ERK kinase (MEK) and EGF receptor; it also attenuated 3 H thymidine incorporation and cell proliferation in VSMC of WKY. In contrast, the effects of AngII were augmented by mechanical stretch in VSMC of SHR. AngII-induced ERK 1/2 phosphorylation and cell proliferation in SHR were inhibited by pretreatment with an AT 1 receptor blocker, candesartan and an inhibitor of MEK, PD98059. Moreover, pretreatment with an EGF receptor tyrosine kinase inhibitor, AG1478, also blocked upregulation of AngII-induced ERK 1/2 phosphorylation induced by stretch in SHR VSMCs. This study demonstrates that mechanical stretch augments SHR VSMC proliferation through an AT 1 /EGF receptor/ERK-dependent pathway. These findings may provide new insights into the signaling mechanisms whereby AngII exerts its growth-promoting effects on vasculature in a hypertensive state.
AB - Angiotensin II (AngII) stimulates vascular smooth muscle cell (VSMC) proliferation; however, the effect of AngII on cell proliferation in the presence of mechanical force is not clear. We investigated the mechanism of AngII-induced cell proliferation mediated by mechanical stretch in VSMCs of both normotensive and hypertensive rats. VSMCs obtained from the thoracic aortas of 8-week-old Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were stretched by a Flex culture system. Mechanical stretch significantly upregulated protein expression of AngII type 1 (AT 1) receptor, epidermal growth factor (EGF) receptor and mitogen-activated protein kinase phosphatase-1 in both SHR and WKY VSMCs; however, there was no significant difference in these changes between the cells from SHR and WKY. Mechanical stretch attenuated AngII-induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, ERK kinase (MEK) and EGF receptor; it also attenuated 3 H thymidine incorporation and cell proliferation in VSMC of WKY. In contrast, the effects of AngII were augmented by mechanical stretch in VSMC of SHR. AngII-induced ERK 1/2 phosphorylation and cell proliferation in SHR were inhibited by pretreatment with an AT 1 receptor blocker, candesartan and an inhibitor of MEK, PD98059. Moreover, pretreatment with an EGF receptor tyrosine kinase inhibitor, AG1478, also blocked upregulation of AngII-induced ERK 1/2 phosphorylation induced by stretch in SHR VSMCs. This study demonstrates that mechanical stretch augments SHR VSMC proliferation through an AT 1 /EGF receptor/ERK-dependent pathway. These findings may provide new insights into the signaling mechanisms whereby AngII exerts its growth-promoting effects on vasculature in a hypertensive state.
KW - angiotensin II
KW - epidermal growth factor receptor
KW - mechanical stretch
KW - spontaneously hypertensive rats
KW - vascular smooth muscle cell
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U2 - 10.1038/hr.2010.187
DO - 10.1038/hr.2010.187
M3 - Article
C2 - 20927110
AN - SCOPUS:78649894020
VL - 33
SP - 1250
EP - 1257
JO - Hypertension Research
JF - Hypertension Research
SN - 0916-9636
IS - 12
ER -