(Hypertension. 1997;30:222-229.)
© 1997 American Heart Association, Inc.
Articles |
Angiotensin II Regulates Vascular Smooth Muscle Cell pH, Contraction, and Growth Via Tyrosine Kinase–Dependent Signaling Pathways
From the Medical Research Council (MRC) Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal (Quebec, Canada).
Correspondence to R.M. Touyz, MD, PhD, 110 Pine Ave W, Montreal, Quebec, Canada H2W 1R7.
Abstract Angiotensin II (Ang II), a potent vasoactive peptide with mitogenic potential, influences vascular smooth muscle cell contraction and growth through receptor-linked pathways that increase intracellular free Ca2+ concentration ([Ca2+]i) and pH (pHi). Activation of these second messengers by Ang II may involve tyrosine kinase-dependent signaling pathways. This study determined the role of tyrosine kinases in Ang II–stimulated pHi, and in simultaneously measured contractile and [Ca2+]i responses, as well as growth in cultured vascular smooth muscle cells from mesenteric arteries of Wistar-Kyoto rats. pHi was determined by fluorescent digital imaging using 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester (BCECF-AM). Vascular smooth muscle cell [Ca2+]i and contractile responses were assessed simultaneously by fura 2 methodology and by photomicroscopy in cells grown on rat tail collagen gels. Cell growth was determined by DNA and protein synthesis as measured by [3H]thymidine and [3H]leucine incorporation, respectively. The Ang II receptor subtypes (AT1 or AT2) through which Ang II mediates effects were assessed with [Sar1,Ile8]Ang II (a nonselective subtype antagonist), losartan (a selective AT1 antagonist), and PD 123319 (a selective AT2 antagonist). To determine whether tyrosine kinases influence Ang II–stimulated responses, cells were pretreated with 10-5 mol/L tyrphostin A-23 (a specific tyrosine kinase inhibitor). Ang II increased pHi in a dose-dependent manner (pD2, 9.2±0.2) and significantly increased vascular smooth muscle cell contraction (30%) and [Ca2+]i (pD2, 7.4±0.1). Ang II (10-7 mol/L) increased DNA ([3H]thymidine incorporation) and protein synthesis ([3H]leucine incorporation). [Sar1,Ile8]Ang II and losartan but not PD 123319 abolished Ang II–elicited responses. Tyrphostin A-23 significantly attenuated Ang II–stimulated pHi responses; it also inhibited [Ca2+]i and contractile responses and cell growth. The inactive analogue tyrphostin A-1 did not alter Ang II–stimulated actions. These results provide novel evidence for a role of tyrosine kinases in Ang II–mediated pHi responses in vascular smooth muscle cells and indicate that tyrosine kinases participate in the regulation of signal transduction associated with AT1 receptor subtype–mediated contraction and growth.
Key Words: calcium • signal transduction • muscle, smooth, vascular • hydrogen-ion concentration
This article has been cited by other articles:
 |
|
 |
|
  S. Sapna, S. K. Ranjith, and K. Shivakumar Cardiac fibrogenesis in magnesium deficiency: a role for circulating angiotensin II and aldosterone Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H436 - H440. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Che and P. K. Carmines Src family kinase involvement in rat preglomerular microvascular contractile and [Ca2+]i responses to ANG II Am J Physiol Renal Physiol, April 1, 2005; 288(4): F658 - F664. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Perlegas, H. Xie, S. Sinha, A. V. Somlyo, and G. K. Owens ANG II type 2 receptor regulates smooth muscle growth and force generation in late fetal mouse development Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H96 - H102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Javeshghani, R. M. Touyz, M. R. Sairam, A. Virdis, M. F. Neves, and E. L. Schiffrin Attenuated Responses to Angiotensin II in Follitropin Receptor Knockout Mice, a Model of Menopause-Associated Hypertension Hypertension, October 1, 2003; 42(4): 761 - 767. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Che and P. K. Carmines Angiotensin II Triggers EGFR Tyrosine Kinase-Dependent Ca2+ Influx in Afferent Arterioles Hypertension, November 1, 2002; 40(5): 700 - 706. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Rossi, A. Ferraresi, P. Romagni, L. Silvestroni, and V. Santiemma Angiotensin II Stimulates Contraction and Growth of Testicular Peritubular Myoid Cells in Vitro Endocrinology, August 1, 2002; 143(8): 3096 - 3104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Cain, D. M. Tanner, and R. A. Khalil Endothelin-1-Induced Enhancement of Coronary Smooth Muscle Contraction via MAPK-Dependent and MAPK-Independent [Ca2+]i Sensitization Pathways Hypertension, February 1, 2002; 39(2): 543 - 549. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Berry, R. Touyz, A. F. Dominiczak, R. C. Webb, and D. G. Johns Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2337 - H2365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. K. Carmines, R. W. Fallet, Q. Che, and K. Fujiwara Tyrosine Kinase Involvement in Renal Arteriolar Constrictor Responses to Angiotensin II Hypertension, February 1, 2001; 37(2): 569 - 573. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Touyz and E. L. Schiffrin Signal Transduction Mechanisms Mediating the Physiological and Pathophysiological Actions of Angiotensin II in Vascular Smooth Muscle Cells Pharmacol. Rev., December 1, 2000; 52(4): 639 - 672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Matrougui, Y. E. G. Eskildsen-Helmond, A. Fiebeler, D. Henrion, B. I. Levy, A. Tedgui, and M. J. Mulvany Angiotensin II Stimulates Extracellular Signal-Regulated Kinase Activity in Intact Pressurized Rat Mesenteric Resistance Arteries Hypertension, October 1, 2000; 36(4): 617 - 621. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D Hughes AT 1-signalling in vascular smooth muscle Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 125 - 130. [PDF]
|
|
|
|
 |
|
 L. Pastore, A. Tessitore, S. Martinotti, E. Toniato, E. Alesse, M. C. Bravi, C. Ferri, G. Desideri, A. Gulino, and A. Santucci Angiotensin II Stimulates Intercellular Adhesion Molecule-1 (ICAM-1) Expression by Human Vascular Endothelial Cells and Increases Soluble ICAM-1 Release In Vivo Circulation, October 12, 1999; 100(15): 1646 - 1652. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Touyz and E. L. Schiffrin Ang II-Stimulated Superoxide Production Is Mediated via Phospholipase D in Human Vascular Smooth Muscle Cells Hypertension, October 1, 1999; 34(4): 976 - 982. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Ford, S. Li, and J. G. Pickering Angiotensin II Stimulates Collagen Synthesis in Human Vascular Smooth Muscle Cells : Involvement of the AT1 Receptor, Transforming Growth Factor-{beta}, and Tyrosine Phosphorylation Arterioscler Thromb Vasc Biol, August 1, 1999; 19(8): 1843 - 1851. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Touyz, G. He, L.-Y. Deng, and E. L. Schiffrin Role of Extracellular Signal-Regulated Kinases in Angiotensin II–Stimulated Contraction of Smooth Muscle Cells From Human Resistance Arteries Circulation, January 26, 1999; 99(3): 392 - 399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Touyz and E. L. Schiffrin Growth Factors Mediate Intracellular Signaling in Vascular Smooth Muscle Cells Through Protein Kinase C–Linked Pathways Hypertension, December 1, 1997; 30(6): 1440 - 1447. [Abstract] [Full Text]
|
|