title: P2Y₂ and Gq/G₁₁ control blood pressure by mediating endothelial mechanotransduction.
abstract: Elevated blood pressure is a key risk factor for developing cardiovascular diseases. Blood pressure is largely determined by vasodilatory mediators, such as nitric oxide (NO), that are released from the endothelium in response to fluid shear stress exerted by the flowing blood. Previous work has identified several mechanotransduction signaling processes that are involved in fluid shear stress-induced endothelial effects, but how fluid shear stress initiates the response is poorly understood. Here, we evaluated human and bovine endothelial cells and found that the purinergic receptor P2Y2 and the G proteins Gq/G11 mediate fluid shear stress-induced endothelial responses, including [Ca2+]i transients, activation of the endothelial NO synthase (eNOS), phosphorylation of PECAM-1 and VEGFR-2, as well as activation of SRC and AKT. In response to fluid shear stress, endothelial cells released ATP, which activates the purinergic P2Y2 receptor. Mice with induced endothelium-specific P2Y2 or Gq/G11 deficiency lacked flow-induced vasodilation and developed hypertension that was accompanied by reduced eNOS activation. Together, our data identify P2Y2 and Gq/G11 as a critical endothelial mechanosignaling pathway that is upstream of previously described mechanotransduction processes and demonstrate that P2Y2 and Gq/G11 are required for basal endothelial NO formation, vascular tone, and blood pressure.
authors.forename: ShengPeng
authors.initials: S
authors.lastname: Wang
authors.forename: András
authors.initials: A
authors.lastname: Iring
authors.forename: Boris
authors.initials: B
authors.lastname: Strilic
authors.forename: Julián
authors.initials: J
authors.lastname: Albarrán Juárez
authors.forename: Harmandeep
authors.initials: H
authors.lastname: Kaur
authors.forename: Kerstin
authors.initials: K
authors.lastname: Troidl
authors.forename: Sarah
authors.initials: S
authors.lastname: Tonack
authors.forename: Joachim C
authors.initials: JC
authors.lastname: Burbiel
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
authors.forename: Jon O
authors.initials: JO
authors.lastname: Lundberg
authors.forename: Nina
authors.initials: N
authors.lastname: Wettschureck
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D002417:Cattle; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D058473:Receptors, Purinergic P2Y2 / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology
chemical_list: D058473:Receptors, Purinergic P2Y2; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C000588866:KDR protein, human; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D043802:GTP-Binding Protein alpha Subunits, Gq-G11