HYPERPLASTIC GROWTH OF AORTIC SMOOTH-MUSCLE CELLS IN RENOVASCULAR HYPERTENSIVE RABBITS IS CHARACTERIZED BY THE EXPANSION OF AN IMMATURE CELL PHENOTYPE

Smooth muscle cells (SMCs) of rabbit aorta undergo marked changes in m yosin isoform content during development. Analysis of nonmuscle myosin composition at the protein level has permitted the identification of three phases in the SMC differentiation process: fetal, postnatal, and adult. Using monoclonal antibodies specific for smooth muscle and non muscle myosins and extra domain A of fibronectin as well as cDNA probe s for platelet-derived growth factors (PDGF) and various procollagens, we have evaluated the differentiation pattern of aortic SMCs in two-k idney, one-clip hypertensive rabbits. Morphometric and bromo-deoxyurid ine studies indicate that hypertrophy of aortic media along with intim al thickening occurring in hypertensive animals is due to SMC hyperpla sia. Western blotting experiments performed on aortic specimens from h ypertensive animals with antimyosin antibodies revealed the appearance of a myosin isoform pattern of the ''immature'' type. Immunofluoresce nce tests showed that these cells are localized in the thickened intim a or distributed in the underlying media (sparsely or in groups). Simi larly, the fibronectin variant showing the extra domain A, peculiar to ''phenotypically modulated'' SMCs, appeared in intimal thickening, an d its expression followed the time course of nonmuscle myosin expressi on. Counting of postnatal-type SMCs in the aortic media revealed that this cell population increases markedly with hypertension (2- up to 15 -fold at 4 months) and then declines to near control level in 8-month hypertensive rabbits. Diminution of postnatal-type SMCs at later stage s of hypertension was temporally correlated with the slowing down of a ortic wall hypertrophy. Average levels of mRNAs, as determined by dens itometric analysis in aortas from 1- and 2.5-month hypertensive rabbit s, showed an increased expression for PDGF beta receptor (up to twofol d), procollagen type I (alpha(1), threefold), procollagen type III (al pha(1), twofold), and fibronectin (up to threefold) compared with cont rols. Conversely, the steady-state levels of mRNAs for PDGF (A and B c hain), PDGF alpha receptor, TGF-beta(1), and procollagen type IV (alph a(1)) did not increase significantly. These results provide evidence t hat in adult renovascular hypertensive rabbits, the hyperplastic growt h of aortic SMCs is accompanied by the expansion of an ''immature'' ce ll phenotype characteristic of the early stages of development.