ANGIOTENSIN-II-INDUCED VASCULAR SMOOTH-MUSCLE CELL HYPERTROPHY - PDGF A-CHAIN MEDIATES THE INCREASE IN CELL-SIZE

We report here that angiotensin II-mediated hypertrophy of vascular smooth muscle cells (VSMC) exhibits PDGF A-chain-dependent and -independent pathways. Secretion of PDGF A-chain is required for the increase in cell size, but not for the increase in protein synthesis. Angiotensin II stimulates a hypertrophic growth response in VSMC characterized by increases in cell size and protein synthesis, but not cell number. Because angiotensin II-stimulated VSMC hypertrophy has been associated with increased PDGF A-chain expression, we studied its role in the hypertrophic response by inhibiting PDGF A-chain expression with hydrocortisone or anti-PDGF antibody. Hydrocortisone (1 muM for 48 h) inhibited basal protein synthesis by 47%, but angiotensin II-stimulated protein synthesis was enhanced (111% increase after hydrocortisone treatment vs. 25% increase in control). In contrast, hypertrophy, as measured by cell size, was completely inhibited. Although hydrocortisone had no effect on early growth signals stimulated by angiotensin II (e.g., activation of protein kinase C, stimulation of Na+/H+ exchange, and c-fos and c-myc expression), it significantly decreased angiotensin II-stimulated secretion of PDGF-like material into the medium from 0.4 to 0.1 ng/ml/24 h (p < 0.01). However, the time course for PDGF secretion (maximal at 16-24 h) was significantly slower than the time course for angiotensin II-stimulated protein synthesis (maximal at 4-12 h). To block the action of PDGF A-chain selectively, VSMC were treated with anti-PDGF A-chain antibody. The antibody completely inhibited the angiotensin II-stimulated increase in cell size, but it had no significant effect on protein synthesis at early times (<8 h). These findings demonstrate two pathways involved in angiotensin II-stimulated VSMC hypertrophy: an increase in cell size dependent on PDGF A-chain and an increase in protein synthesis independent of PDGF A-chain.