GROWTH-SUPPRESSIVE MECHANISMS IN VASCULAR SMC

描述（改编自申请人摘要）：多种血管

DESCRIPTION (Adapted from Applicant's Abstract):A number of vascular disease states including arteriosclerosis, systemic and pulmonary hypertension, and the restenosis of vascular grafts, reconstructions, and endarterectomies are characterized by the abnormal or unregulated replication of tunica media-derived smooth muscle cells (SMC), whose proliferation is normally tightly restricted. In this application the investigators propose to study the mechanisms underlying the acquisition of the quiescent phenotype which typifies SMC in the adult vascular wall. They present preliminary data which show that SMC forming the tunica media of the fetal rat aorta (Day 17p.c.) exhibit a very high replication rate in vivo (>95%); this replication rate falls dramatically to <5% by fetal Day 19. Fetal SMC cultured from the truncus arteriosus (fetal Days 13-14) or aorta (fetal Day 17) exhibited heritable autocrine growth characteristics and replicated freely under serum deprived conditions. In contrast, SMC cultured from later stage embryos (fetal Day 20 or 21) or from neonates were dependent on serum for replication in vitro. The data suggest that SMC undergo a phenotypic switch from autocrine to non- autocrine growth at some point in late fetal development. They propose to determine the molecular basis for the loss of autocrine growth potential. Specifically, they plan:i) to determine the pattern of cell replication in the fetal, neonatal, and adult rat aorta, ii) to culture SMC from fetal aortas of increasing developmental ages and determine the exact point at which autocrine growth potential is lost, iii) to determine the growth factor(s) responsible for driving autocrine growth in cultured fetal SMC, iv) to determine the changes in gene expression which underlie the loss of autocrine growth potential, and v) to determine if similar changes in gene expression occur in vivo. Their ultimate goal is to understand the mechanisms which mediate SMC growth suppression in the normal vessel wall, with the understanding that the elucidation of specific endogenous growth suppressing mechanisms may provide a basis for the eventual development of effective therapeutic strategies for the treatment of vascular diseases involving unregulated SMC replication.