The　upregulation　of　Sphingosine　kinase　1　(SphK1)　expression　and　accompanied　sphingosine-1-phosphate　(S1P)　production　have　been　reported　to　contribute　to　the　proliferation　of　pulmonary　artery　smooth　muscle　cells　(PASMC)　and　pulmonary　arterial　remodeling.　However,　the　molecular　mechanisms　of　SphK1/S1P　upregulation　in　PASMC　and　the　specific　mechanisms　of　how　SphK1/S1P　pathway　promotes　PASMC　proliferation　remain　largely　unclear.　This　study　aims　to　address　these　issues.　Here,　we　demonstrated　that　TGF-beta　1　significantly　upregulated　SphK1　expression　and　S1P　production　by　promoting　the　phosphorylation　of　Smad2/3　in　PASMC.　Further　study　indicated　that　SphK1/S1P　pathway　mediated　TGF-beta　1-induced　Notch3　activation　in　PASMC.　In　addition,　we　showed　that　TGF-beta　1　significantly　induced　proliferation　of　PASMC,　while　pre-inhibition　of　Smad2/3　phosphorylation　with　SB431542　or　silencing　SphK1　using　small　interfering　RNA　in　advance,　or　pre-blocking　Notch3　pathway　with　N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine　t-butyl　ester　(DAPT),　attenuated　TGF-beta　1-induced　PASMC　proliferation.　Taken　together,　our　study　indicates　that　Smad2/3/SphK1/S1P/Notch3　pathway　mediates　TGF-beta　1-induced　PASMC　proliferation　and　suggests　this　pathway　as　a　potential　therapeutic　target　in　the　prevention　and　treatment　of　pulmonary　hypertension.