Activation　of　the　Notch3　cascade　is　involved　in　the　development　of　pulmonary　arterial　hypertension　by　stimulating　the　proliferation　of　vascular　smooth　muscle　cells.　However,　the　detailed　molecular　mechanisms　underlying　this　effect　are　still　unclear.　The　present　study　aims　to　address　this　issue.　We　demonstrated　that　over-expression　of　intracellular　domain　of　the　Notch3　receptor　(NICD3)　by　adenovirus　transfection　dramatically　induced　proliferation　of　primary　cultured　pulmonary　artery　smooth　muscle　cells.　This　was　accompanied　with　up-regulation　of　Hes1　protein　and　down-regulation　of　p27Kip1　protein.　More　importantly,　we　observed　that　prior　silencing　of　Hes1　with　siRNA　blocked　NICD3　over-expression-induced　p27Kip1　reduction　and　cell　proliferation.　The　present　study　suggests　that　Hes1　lies　downstream　of　NICD3　and　particularly　mediates　Notch3　signaling-induced　proliferation　of　pulmonary　arterial　smooth　muscle　cells　by　down-regulation　of　p27Kip1　expression.　(C)　2015　The　Authors.　Published　by　Elsevier　B.V.　on　behalf　of　the　Federation　of　European　Biochemical　Societies.