Concerted effects of lipoproteins and angiotensin II on signal transduction processes in vascular smooth muscle cells

V N Bochkov, V A Tkachuk, A W Hahn, J Bernhardt, F R Buhler, T J Resink
1993 Arteriosclerosis and Thrombosis A Journal of Vascular Biology  
Low-density (LDL) and high-density (HDLj) lipoproteins dose-dependently activate phosphoinositide turnover and elevate cytosolic free Ca 2+ concentrations ([Ca 1+ ]|) in cultured vascular smooth muscle cells (VSMCs) from either human (microarterioles and aorta) or rat (aorta) sources. High-performance liquid chromatography analysis of cell extracts revealed comparable spectra of inositol phosphate isomers generated in response to either LDL, HDL" or angiotensin II (Ang II). Thus, lipoproteins
more » ... d Ang II may use similar, if not identical, signal transduction pathways for the generation and metabolism of inositol phosphates and intracellular Ca 2+ mobilization in VSMCs. When Ang II was added in combination with either LDL or HDL], the phosphoinositide and fCa 2+ ], responses of VSMCs were either equal to or even greater than the sum of the effects elicited by the agonists individually. This additivity/synergy between Ang II and the lipoproteins was not accompanied by alteration in the half-maximally effective dose requirements of VSMCs for either Ang II (<=>2 nmol/L, with or without lipoproteins) or lipoproteins (=50 figjmh for LDL and HDL" with or without Ang II). Neither short-term (up to 10 minutes) nor long-term (48 hours) exposure of VSMCs to lipoproteins caused desensitization of phospholipase C and intracellular Ca 1+ mobilization responses to either Ang II or lipoproteins. Since constant exposure of VSMCs to lipoproteins is a physiological circumstance, and because elevation of [Ca 2+ ], and activation of phosphoinositide turnover are pivotal events for VSMC contraction and growth, we suggest that the low concentrations of lipoproteins in the vessel intlma may play an important role in regulating the response of the vasculature to Ang II. (ArUriosder Thromb. 1993;13:1261-1269 KEY WORDS • lipoproteins • smooth muscle cells • angiotensin II • intracellular calcium • inositol phosphate isomers A ccelerated vascular smooth muscle cell (VSMC) / \ growth plays a fundamental role in atheroscle-A. A . rotic lesion formation and is a characteristic feature in arteries from hypertensive patients and animals. 10 Epidemiologic studies also show that hypertension is a major risk factor for development of atherosclerosis. 4 Different hypotheses have been proposed to explain the association between the two diseases, with the common etiologic denominators being either disturbances in plasma lipoprotein concentrations and cellular cholesterol homeostasis, 5 intracellular calcium overload, 6 or altered responses to growth factors and vasoregulatory hormones. 1 -3 These theories are not mutually exclusive, however, and linkage between the latter two is predictable because growth factors and vasoregulatory hormones are known to mobilize intracellular calcium. The relation between lipoprotein/cholesterol disturbances and the calcium-based or agonist growth factor-based theories is less conspicuous, but it
doi:10.1161/01.atv.13.9.1261 fatcat:h4y34nb3ynhnhf4c5yehnrqza4