The effects of low density lipoprotein (LDL) and high density lipoprotein (HDL 3) on second messenger systems were investigated in cultured human vascular smooth muscle cells (VSMC) and compared with those of angiotensin II (Ang II) and platelet-derived growth factor (PDGF-BB). Phosphoinositide metabolism was studied in myo-[2- 3H]-inositol prelabelled VSMC using high performance liquid anionexchange chromatography. The spectra of inositol phosphate isomers increased after stimulation with either Ang II, LDL, HDL 3, or PDGF-BB were qualitatively identical. Major increases occurred in 4-IP 1, 1,4-IP 2, 1,3,4-IP 3 and 1,3,4,5-IP 4. These are metabolic conversion products of 1,4,5-IP 3 for which only a minor increase was found. Thus lipoproteins, like Ang II and PDGF-BB, activate polyphosphatidylinositol-specific phospholipase C. Intracellular Ca 2+ concentrations ([Ca 2+] ii) were studied in fura-2 loaded VSMC. In monolayer cultures LDL and HDL 3 increased [Ca 2+] i with kinetics comparable to those for Ang II. Relative to the effects of these agonists, the PDGF-BB-induced increase in [Ca 2+] i was slower in onset and the decay from peak [Ca 2+] i levels more gradual. Fluorescence recordings from single cells exposed to LDL and HDL 3 revealed a prolonged series of transient oscillations of [Ca 2+] i, a phenomenon typical for calcium-mobilizing hormones. Additionally, as found for Ang II, preincubation of VSMC with either phorbol 12-myristate, 13-acetate, forskolin or 8-bromo-cyclic GMP inhibited LDL, and HDL-induced accumulation of [ 3H]-inositol monophosphate. We propose that LDL and HDL 3 stimulate signal transduction in VSMC via mechanisms analogous to those of C 2+-mobilizing hormones.