SMOOTH MUSCLE CELL (SMC) PROLIFERATION AND DIFFERENTIATION CONTRIBUTES TO SEVERAL VASCULAR DISEASES, SUCH AS ATHEROSCLEROSIS, POST-TRANSPLANT VASCULOPATHY, RESTENOSIS AFTER ANGIOPLASTY, ETC. DELAYED RE-ENDOTHELIALIZATION AND VASCULAR REPAIR ARE COMMON RESULTS OF CARDIOVASCULAR INTERVENTION, SUCH AS IMPLANTATION OF DRUG-ELUTING STENTS, DUE TO THE INHIBITORY EFFECT OF ANTI-PROLIFERATIVE DRUGS ON ENDOTHELIAL CELL PROLIFERATION. THEREFORE, IDENTIFYING NOVEL MOLECULAR MECHANISMS THAT DIFFERENTIALLY REGULATE THE PROLIFERATION OF SMCS AND ECS IS IMPORTANT FOR DEVELOPING NEW THERAPEUTICS FOR PROPER VASCULAR REPAIR. OBJECTIVE OF THIS STUDY IS TO DETERMINE THE ROLE AND MECHANISM OF JANUS KINASE 3 (JAK3) AND BRAIN CYTOPLASMIC RNA 1 (BC1) IN SMC PROLIFERATION AND DIFFERENTIATION. JAK3 INDUCES SMC PROLIFERATION WHILE SUPPRESSES EC PROLIFERATION. A RELATIVELY HIGHER EXPRESSION OF JAK3 IN ECS THAN SMCS AT QUIESCENT STAGE IS OBSERVED. HOWEVER, JAK3 IS INDUCED IN PROLIFERATIVE SMCS BUT DECREASED IN PROLIFERATIVE ECS. MECHANISTICALLY, JAK3 PROMOTES SMC PROLIFERATION VIA ACTIVATION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 AND C-JUN N-TERMINAL KINASE. CONVERSELY, JAK3 INHIBITS EC PROLIFERATION VIA TWO PATHWAYS. FIRSTLY, JAK3 REGULATES EC PROLIFERATION BY ALTERING THE EXPRESSION OF PRO- AND ANTI-ANGIOGENIC FACTORS, VASCULAR ENDOTHELIAL GROWTH FACTOR A AND THROMBOSPONDIN 1, RESPECTIVELY. SECONDLY, JAK3 ARRESTS CELL CYCLE PROGRESSION OF EC AT G0/G1 STAGE BY DIMINISHING THE STABILITY OF G1-S TRANSITION REGULATOR, CYCLIN E. IN VIVO, KNOCKDOWN OF JAK3 REDUCES INJURY-INDUCED NEOINTIMAL FORMATION ALONG WITH ACCELERATION OF RE-ENDOTHELIALIZATION. OUR RESULTS DEMONSTRATE THAT JAK3 PLAYS AN OPPOSITE ROLE IN REGULATING SMC AND EC PROLIFERATION IN RESPONSE TO VASCULAR INJURY. SMC DIFFERENTIATION IS AN ESSENTIAL PROCESS NOT ONLY IN VASCULAR DEVELOPMENT, BUT ALSO THE PROGRESSION OF VASCULAR DISEASES. WE FOUND THAT LONG NON-CODING RNA BC1 IS A CRITICAL REGULATOR FOR THIS PROCESS. MECHANISTICALLY, BC1 BINDS TO SMAD3 VIA RNA SMAD-BINDING ELEMENTS (RSBES) AND THUS IMPEDES TGF-β-induced SMAD3 NUCLEAR TRANSLOCATION, WHICH PREVENTS SMAD3 FROM BINDING TO SBE IN SMC MARKER GENE PROMOTERS. IN VIVO, OVEREXPRESSION OF BC1 IN MOUSE EMBRYO IMPAIRS VASCULAR SMC DIFFERENTIATION, CAUSING DEFECTIVE ARTERY DEVELOPMENT SUCH AS RANDOM BREAKS OF ELASTIC LAMINA, INORDINATE STACK OF SMCS, AND UNORGANIZED EXTRA CELLULAR MATRIX PROTEINS IN THE MEDIA OF NEONATAL AORTA. OUR RESULTS SUGGEST THAT BC1 IS A NEGATIVE REGULATOR FOR SMC DIFFERENTIATION DURING VASCULAR DEVELOPMENT.