Tyrosine Kinase Signaling Pathways Modulate Angiotensin II–Induced Calcium ([Ca 2+ ] i ) Transients in Vascular Smooth Muscle Cells

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Abstract
Tyrosine kinases have been implicated in vascular smooth muscle cell proliferation and contraction. Underlying mechanisms may involve Ca 2+ -dependent pathways. This study assesses relationships between angiotensin II (Ang II)–stimulated phospholipase C–mediated Ca 2+ transients and tyrosine kinase–dependent pathways in vascular smooth muscle cells. Intracellular free Ca 2+ concentration ([Ca 2+ ] i ) was measured in primary cultured unpassaged vascular smooth muscle cells derived from mesenteric resistance vessels of Wistar-Kyoto rats with the use of fura 2 methodology. [Ca 2+ ] i effects of Ang II (1 nmol/L) were determined in vascular smooth muscle cells in which tyrosine kinase pathways were stimulated by insulin (70 μU/mL; 0.5 nmol/L), insulin-like growth factor-I (1 ng/mL; 0.13 nmol/L), or platelet-derived growth factor-BB (1 ng/mL; 0.04 nmol/L) and in cells in which tyrosine kinase was inhibited by specific inhibitors (1 μmol/L tyrphostin A-23 and genistein). Ang II elicited a rapid and transient [Ca 2+ ] i response (from 94±8 to 239±5.8 nmol/L). Activation of the receptor tyrosine kinase by insulin, platelet-derived growth factor, and insulin-like growth factor-I significantly reduced ( P <.01) Ang II–induced [Ca 2+ ] i to 161±7, 189±3.7, and 183±5 nmol/L, respectively. In the presence of tyrphostin A-23 and genistein, Ang II–stimulated [Ca 2+ ] i remained persistently elevated and failed to return to basal levels. Tyrphostin A-1, the inactive tyrphostin analogue, had no significant effect on Ang II–induced [Ca 2+ ] i. This study demonstrates that activation of tyrosine kinase pathways reduces Ang II–elicited [Ca 2+ ] i responses, whereas tyrosine kinase inhibition prevents [Ca 2+ ] i recovery after agonist stimulation. Interaction between tyrosine kinase– and phospholipase C–dependent signaling pathways modulates vascular smooth muscle cell [Ca 2+ ] i responses to Ang II.

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