{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T02:49:07Z","timestamp":1791341347129,"version":"4.3.1"},"reference-count":101,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2003,9]]},"abstract":"<jats:p>Vascular endothelial cells are directly and continuously exposed to fluid shear stress generated by blood flow. Shear stress regulates endothelial structure and function by controlling expression of mechanosensitive genes and production of vasoactive factors such as nitric oxide (NO). Though it is well known that shear stress stimulates NO production from endothelial nitric oxide synthase (eNOS), the underlying molecular mechanisms remain unclear and controversial. Shear-induced production of NO involves Ca<jats:sup>2<\/jats:sup><jats:sup>+<\/jats:sup>\/calmodulin-independent mechanisms, including phosphorylation of eNOS at several sites and its interaction with other proteins, including caveolin and heat shock protein-90. There have been conflicting results as to which protein kinases\u2014protein kinase A, protein kinase B (Akt), other Ser\/Thr protein kinases, or tyrosine kinases\u2014are responsible for shear-dependent eNOS regulation. The functional significance of each phosphorylation site is still unclear. We have attempted to summarize the current status of understanding in shear-dependent eNOS regulation.<\/jats:p>","DOI":"10.1152\/ajpcell.00122.2003","type":"journal-article","created":{"date-parts":[[2013,5,14]],"date-time":"2013-05-14T00:16:02Z","timestamp":1368490562000},"page":"C499-C508","source":"Crossref","is-referenced-by-count":319,"title":["Flow-dependent regulation of endothelial nitric oxide synthase: role of protein kinases"],"prefix":"10.1152","volume":"285","author":[{"given":"Yong Chool","family":"Boo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanjoong","family":"Jo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"REF1","doi-asserted-by":"crossref","unstructured":"Alderton WK, Cooper CE, and Knowles RG.Nitric oxide synthases: structure, function and inhibition.Biochem J357: 593\u2013615, 2001.","DOI":"10.1042\/bj3570593"},{"key":"REF2","unstructured":"Awolesi MA, Widmann MD, Sessa WC, and Sumpio BE.Cyclic strain increases endothelial nitric oxide synthase activity.Surgery116: 439\u2013445, 1994."},{"key":"REF3","doi-asserted-by":"crossref","unstructured":"Ayajiki K, Kindermann M, Hecker M, Fleming I, and Busse R.Intracellular pH and tyrosine phosphorylation but not calcium determine shear stress-induced nitric oxide production in native endothelial cells.Circ Res78: 750\u2013758, 1996.","DOI":"10.1161\/01.RES.78.5.750"},{"key":"REF4","doi-asserted-by":"crossref","unstructured":"Boo YC, Hwang J, Sykes M, Michell BJ, Kemp BE, Lum H, and Jo H.Shear stress stimulates phosphorylation of eNOS at Ser635by a protein kinase A-dependent mechanism.Am J Physiol Heart Circ Physiol283: H1819\u2013H1828, 2002.","DOI":"10.1152\/ajpheart.00214.2002"},{"key":"REF5","unstructured":"Boo YC, Sorescu GP, Bauer PM, Fulton D, Kemp BE, Harrison DG, Sessa WC, and Jo H.Phosphorylation of eNOS at Ser635 stimulates NO production in a Ca2+-independent manner (Abstract).FASEB J17: A805, 2003."},{"key":"REF6","doi-asserted-by":"crossref","unstructured":"Boo YC, Sorescu G, Boyd N, Shiojima I, Walsh K, Du J, and Jo H.Shear stress stimulates phosphorylation of endothelial nitric-oxide synthase at Ser1179 by Akt-independent mechanisms: role of protein kinase A.J Biol Chem277: 3388\u20133396, 2002.","DOI":"10.1074\/jbc.M108789200"},{"key":"REF7","doi-asserted-by":"crossref","unstructured":"Bredt DS.Endogenous nitric oxide synthesis: biological functions and pathophysiology.Free Radic Res31: 577\u2013596, 1999.","DOI":"10.1080\/10715769900301161"},{"key":"REF8","doi-asserted-by":"crossref","unstructured":"Bredt DS, Ferris CD, and Snyder SH.Nitric oxide synthase regulatory sites. Phosphorylation by cyclic AMP-dependent protein kinase, protein kinase C, and calcium\/calmodulin protein kinase; identification of flavin and calmodulin binding sites.J Biol Chem267: 10976\u201310981, 1992.","DOI":"10.1016\/S0021-9258(19)49862-1"},{"key":"REF9","doi-asserted-by":"crossref","unstructured":"Brouet A, Sonveaux P, Dessy C, Balligand JL, and Feron O.Hsp90 ensures the transition from the early Ca2+-dependent to the late phosphorylation-dependent activation of the endothelial nitric-oxide synthase in vascular endothelial growth factor-exposed endothelial cells.J Biol Chem276: 32663\u201332669, 2001.","DOI":"10.1074\/jbc.M101371200"},{"key":"REF10","doi-asserted-by":"crossref","unstructured":"Busse Rand Mulsch A.Calcium-dependent nitric oxide synthesis in endothelial cytosol is mediated by calmodulin.FEBS Lett265: 133\u2013136, 1990.","DOI":"10.1016\/0014-5793(90)80902-U"},{"key":"REF11","doi-asserted-by":"crossref","unstructured":"Butt E, Bernhardt M, Smolenski A, Kotsonis P, Frohlich LG, Sickmann A, Meyer HE, Lohmann SM, and Schmidt HH.Endothelial nitric-oxide synthase (type III) is activated and becomes calcium independent upon phosphorylation by cyclic nucleotide-dependent protein kinases.J Biol Chem275: 5179\u20135187, 2000.","DOI":"10.1074\/jbc.275.7.5179"},{"key":"REF12","doi-asserted-by":"crossref","unstructured":"Cai H, Li Z, Davis ME, Kanner W, Harrison DG, and Dudley SC Jr.Akt-dependent phosphorylation of serine 1179 and mitogen-activated protein kinase kinase\/extracellular signal-regulated kinase 1\/2 cooperatively mediate activation of the endothelial nitric-oxide synthase by hydrogen peroxide.Mol Pharmacol63: 325\u2013331, 2003.","DOI":"10.1124\/mol.63.2.325"},{"key":"REF13","doi-asserted-by":"crossref","unstructured":"Cao S, Yao J, McCabe TJ, Yao Q, Katusic ZS, Sessa WC, and Shah V.Direct interaction between endothelial nitricoxide synthase and dynamin-2. Implications for nitric-oxide synthase function.J Biol Chem276: 14249\u201314256, 2001.","DOI":"10.1074\/jbc.M006258200"},{"key":"REF14","doi-asserted-by":"crossref","unstructured":"Cauthron RD, Carter KB, Liauw S, and Steinberg RA.Physiological phosphorylation of protein kinase A at Thr-197 is by a protein kinase A kinase.Mol Cell Biol18: 1416\u20131423, 1998.","DOI":"10.1128\/MCB.18.3.1416"},{"key":"REF15","doi-asserted-by":"crossref","unstructured":"Chen PFand Wu KK.Characterization of the roles of the 594\u2013645 region in human endothelial nitric-oxide synthase in regulating calmodulin binding and electron transfer.J Biol Chem275: 13155\u201313163, 2000.","DOI":"10.1074\/jbc.275.17.13155"},{"key":"REF16","doi-asserted-by":"crossref","unstructured":"Chen ZP, Mitchelhill KI, Michell BJ, Stapleton D, Rodriguez-Crespo I, Witters LA, Power DA, Ortiz de Montellano PR, and Kemp BE.AMP-activated protein kinase phosphorylation of endothelial NO synthase.FEBS Lett443: 285\u2013289, 1999.","DOI":"10.1016\/S0014-5793(98)01705-0"},{"key":"REF17","doi-asserted-by":"crossref","unstructured":"Cheng X, Ma Y, Moore M, Hemmings BA, and Taylor SS.Phosphorylation and activation of cAMP-dependent protein kinase by phosphoinositide-dependent protein kinase.Proc Natl Acad Sci USA95: 9849\u20139854, 1998.","DOI":"10.1073\/pnas.95.17.9849"},{"key":"REF18","doi-asserted-by":"crossref","unstructured":"Cho HJ, Xie QW, Calaycay J, Mumford RA, Swiderek KM, Lee TD, and Nathan C.Calmodulin is a subunit of nitric oxide synthase from macrophages.J Exp Med176: 599\u2013604, 1992.","DOI":"10.1084\/jem.176.2.599"},{"key":"REF19","doi-asserted-by":"crossref","unstructured":"Corson MA, James NL, Latta SE, Nerem RM, Berk BC, and Harrison DG.Phosphorylation of endothelial nitric oxide synthase in response to fluid shear stress.Circ Res79: 984\u2013991, 1996.","DOI":"10.1161\/01.RES.79.5.984"},{"key":"REF20","doi-asserted-by":"crossref","unstructured":"Darley-Usmar Vand Halliwell B.Blood radicals: reactive nitrogen species, reactive oxygen species, transition metal ions, and the vascular system.Pharm Res13: 649\u2013662, 1996.","DOI":"10.1023\/A:1016079012214"},{"key":"REF21","doi-asserted-by":"crossref","unstructured":"Davda RK, Chandler LJ, and Guzman NJ.Protein kinase C modulates receptor-independent activation of endothelial nitric oxide synthase.Eur J Pharmacol266: 237\u2013244, 1994.","DOI":"10.1016\/0922-4106(94)90132-5"},{"key":"REF22","doi-asserted-by":"crossref","unstructured":"Davies PF.Flow-mediated endothelial mechanotransduction.Physiol Rev75: 519\u2013560, 1995.","DOI":"10.1152\/physrev.1995.75.3.519"},{"key":"REF23","doi-asserted-by":"crossref","unstructured":"Davis ME, Cai H, Drummond GR, and Harrison DG.Shear stress regulates endothelial nitric oxide synthase expression through c-Src by divergent signaling pathways.Circ Res89: 1073\u20131080, 2001.","DOI":"10.1161\/hh2301.100806"},{"key":"REF24","doi-asserted-by":"crossref","unstructured":"Davis ME, Cai H, McCann L, Fukai T, and Harrison DG.Role of c-Src in regulation of endothelial nitric oxide synthase expression during exercise training.Am J Physiol Heart Circ Physiol284: H1449\u2013H1453, 2003.","DOI":"10.1152\/ajpheart.00918.2002"},{"key":"REF25","doi-asserted-by":"crossref","unstructured":"De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA Jr, Shin WS, and Liao JK.Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines.J Clin Invest96: 60\u201368, 1995.","DOI":"10.1172\/JCI118074"},{"key":"REF26","doi-asserted-by":"crossref","unstructured":"Dedio J, Konig P, Wohlfart P, Schroeder C, Kummer W, and Muller-Esterl W.NOSIP, a novel modulator of endothelial nitric oxide synthase activity.FASEB J15: 79\u201389, 2001.","DOI":"10.1096\/fj.00-0078com"},{"key":"REF27","doi-asserted-by":"crossref","unstructured":"De Nadai C, Sestili P, Cantoni O, Lievremont JP, Sciorati C, Barsacchi R, Moncada S, Meldolesi J, and Clementi E.Nitric oxide inhibits tumor necrosis factor-alpha-induced apoptosis by reducing the generation of ceramide.Proc Natl Acad Sci USA97: 5480\u20135485, 2000.","DOI":"10.1073\/pnas.070062397"},{"key":"REF28","doi-asserted-by":"crossref","unstructured":"Dimmeler S, Assmus B, Hermann C, Haendeler J, and Zeiher AM.Fluid shear stress stimulates phosphorylation of Akt in human endothelial cells: involvement in suppression of apoptosis.Circ Res83: 334\u2013341, 1998.","DOI":"10.1161\/01.RES.83.3.334"},{"key":"REF29","doi-asserted-by":"crossref","unstructured":"Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, and Zeiher AM.Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation.Nature399: 601\u2013605, 1999.","DOI":"10.1038\/21224"},{"key":"REF30","doi-asserted-by":"crossref","unstructured":"Dimmeler S, Haendeler J, Nehls M, and Zeiher AM.Suppression of apoptosis by nitric oxide via inhibition of interleukin-1beta-converting enzyme (ICE)-like and cysteine protease protein (CPP)-32-like proteases.J Exp Med185: 601\u2013607, 1997.","DOI":"10.1084\/jem.185.4.601"},{"key":"REF31","doi-asserted-by":"crossref","unstructured":"Dimmeler S, Hermann C, Galle J, and Zeiher AM.Upregulation of superoxide dismutase and nitric oxide synthase mediates the apoptosis-suppressive effects of shear stress on endothelial cells.Arterioscler Thromb Vasc Biol19: 656\u2013664, 1999.","DOI":"10.1161\/01.ATV.19.3.656"},{"key":"REF32","doi-asserted-by":"crossref","unstructured":"Drummond GR, Cai H, Davis ME, Ramasamy S, and Harrison DG.Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hydrogen peroxide.Circ Res86: 347\u2013354, 2000.","DOI":"10.1161\/01.RES.86.3.347"},{"key":"REF33","doi-asserted-by":"crossref","unstructured":"Dulin NO, Niu J, Browning DD, Ye RD, and Voyno-Yasenetskaya T.Cyclic AMP-independent activation of protein kinase A by vasoactive peptides.J Biol Chem276: 20827\u201320830, 2001.","DOI":"10.1074\/jbc.C100195200"},{"key":"REF34","doi-asserted-by":"crossref","unstructured":"Dull ROand Davies PF.Flow modulation of agonist (ATP)-response (Ca2+) coupling in vascular endothelial cells.Am J Physiol Heart Circ Physiol261: H149\u2013H154, 1991.","DOI":"10.1152\/ajpheart.1991.261.1.H149"},{"key":"REF35","doi-asserted-by":"crossref","unstructured":"Fleming I, Bauersachs J, and Busse R.Calcium-dependent and calcium-independent activation of the endothelial NO synthase.J Vasc Res34: 165\u2013174, 1997.","DOI":"10.1159\/000159220"},{"key":"REF36","doi-asserted-by":"crossref","unstructured":"Fleming I, Bauersachs J, Fisslthaler B, and Busse R.Ca2+-independent activation of the endothelial nitric oxide synthase in response to tyrosine phosphatase inhibitors and fluid shear stress.Circ Res82: 686\u2013695, 1998.","DOI":"10.1161\/01.RES.82.6.686"},{"key":"REF37","doi-asserted-by":"crossref","unstructured":"Fleming Iand Busse R.Signal transduction of eNOS activation.Cardiovasc Res43: 532\u2013541, 1999.","DOI":"10.1016\/S0008-6363(99)00094-2"},{"key":"REF38","doi-asserted-by":"crossref","unstructured":"Fleming Iand Busse R.Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase.Am J Physiol Regul Integr Comp Physiol284: R1\u2013R12, 2003.","DOI":"10.1152\/ajpregu.00323.2002"},{"key":"REF39","doi-asserted-by":"crossref","unstructured":"Fleming I, Fisslthaler B, Dimmeler S, Kemp BE, and Busse R.Phosphorylation of Thr495regulates Ca2+\/calmodulin-dependent endothelial nitric oxide synthase activity.Circ Res88: E68\u2013E75, 2001.","DOI":"10.1161\/hh1101.092677"},{"key":"REF40","doi-asserted-by":"crossref","unstructured":"Franke TF, Kaplan DR, and Cantley LC.PI3K: downstream AKTion blocks apoptosis.Cell88: 435\u2013437, 1997.","DOI":"10.1016\/S0092-8674(00)81883-8"},{"key":"REF41","doi-asserted-by":"crossref","unstructured":"Fulton D, Fontana J, Sowa G, Gratton JP, Lin M, Li KX, Michell B, Kemp BE, Rodman D, and Sessa WC.Localization of endothelial nitric-oxide synthase phosphorylated on serine 1179 and nitric oxide in Golgi and plasma membrane defines the existence of two pools of active enzyme.J Biol Chem277: 4277\u20134284, 2002.","DOI":"10.1074\/jbc.M106302200"},{"key":"REF42","doi-asserted-by":"crossref","unstructured":"Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, and Sessa WC.Regulation of endothelium-derived nitric oxide production by the protein kinase Akt.Nature399: 597\u2013601, 1999.","DOI":"10.1038\/21218"},{"key":"REF43","doi-asserted-by":"crossref","unstructured":"Fulton D, Gratton JP, and Sessa WC.Post-translational control of endothelial nitric oxide synthase: why isn't calcium\/calmodulin enough?J Pharmacol Exp Ther299: 818\u2013824, 2001.","DOI":"10.1016\/S0022-3565(24)29198-9"},{"key":"REF44","doi-asserted-by":"crossref","unstructured":"Furchgott RFand Zawadzki JV.The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.Nature288: 373\u2013376, 1980.","DOI":"10.1038\/288373a0"},{"key":"REF45","doi-asserted-by":"crossref","unstructured":"Gachhui R, Abu-Soud HM, Ghosha DK, Presta A, Blazing MA, Mayer B, George SE, and Stuehr DJ.Neuronal nitricoxide synthase interaction with calmodulin-troponin C chimeras.J Biol Chem273: 5451\u20135454, 1998.","DOI":"10.1074\/jbc.273.10.5451"},{"key":"REF46","doi-asserted-by":"crossref","unstructured":"Gallis B, Corthals GL, Goodlett DR, Ueba H, Kim F, Presnell SR, Figeys D, Harrison DG, Berk BC, Aebersold R, and Corson MA.Identification of flow-dependent endothelial nitric-oxide synthase phosphorylation sites by mass spectrometry and regulation of phosphorylation and nitric oxide production by the phosphatidylinositol 3-kinase inhibitor LY294002.J Biol Chem274: 30101\u201330108, 1999.","DOI":"10.1074\/jbc.274.42.30101"},{"key":"REF47","doi-asserted-by":"crossref","unstructured":"Garcia-Cardena G, Fan R, Shah V, Sorrentino R, Cirino G, Papapetropoulos A, and Sessa WC.Dynamic activation of endothelial nitric oxide synthase by Hsp90.Nature392: 821\u2013824, 1998.","DOI":"10.1038\/33934"},{"key":"REF48","doi-asserted-by":"crossref","unstructured":"Garcia-Cardena G, Fan R, Stern DF, Liu J, and Sessa WC.Endothelial nitric oxide synthase is regulated by tyrosine phosphorylation and interacts with caveolin-1.J Biol Chem271: 27237\u201327240, 1996.","DOI":"10.1074\/jbc.271.44.27237"},{"key":"REF49","doi-asserted-by":"crossref","unstructured":"Gimbrone MAJr, Topper JN, Nagel T, Anderson KR, and Garcia-Cardena G.Endothelial dysfunction, hemodynamic forces, and atherogenesis.Ann NY Acad Sci902: 230\u2013240, 2000.","DOI":"10.1111\/j.1749-6632.2000.tb06318.x"},{"key":"REF50","doi-asserted-by":"crossref","unstructured":"Go YM, Boo YC, Park H, Maland MC, Patel R, Pritchard KA Jr, Fujio Y, Walsh K, Darley-Usmar V, and Jo H.Protein kinase B\/Akt activates c-Jun NH2-terminal kinase by increasing NO production in response to shear stress.J Appl Physiol91: 1574\u20131581, 2001.","DOI":"10.1152\/jappl.2001.91.4.1574"},{"key":"REF51","doi-asserted-by":"crossref","unstructured":"Go YM, Park H, Maland MC, Darley-Usmar VM, Stoyanov B, Wetzker R, and Jo H.Phosphatidylinositol 3-kinase \u03b3 mediates shear stress-dependent activation of JNK in endothelial cells.Am J Physiol Heart Circ Physiol275: H1898\u2013H1904, 1998.","DOI":"10.1152\/ajpheart.1998.275.5.H1898"},{"key":"REF52","doi-asserted-by":"crossref","unstructured":"Harris MB, Ju H, Venema VJ, Liang H, Zou R, Michell BJ, Chen ZP, Kemp BE, and Venema RC.Reciprocal phosphorylation and regulation of endothelial nitric-oxide synthase in response to bradykinin stimulation.J Biol Chem276: 16587\u201316591, 2001.","DOI":"10.1074\/jbc.M100229200"},{"key":"REF53","doi-asserted-by":"crossref","unstructured":"Hermann C, Zeiher AM, and Dimmeler S.Shear stress inhibits H2O2-induced apoptosis of human endothelial cells by modulation of the glutathione redox cycle and nitric oxide synthase.Arterioscler Thromb Vasc Biol17: 3588\u20133592, 1997.","DOI":"10.1161\/01.ATV.17.12.3588"},{"key":"REF54","doi-asserted-by":"crossref","unstructured":"Hirata K, Kuroda R, Sakoda T, Katayama M, Inoue N, Suematsu M, Kawashima S, and Yokoyama M.Inhibition of endothelial nitric oxide synthase activity by protein kinase C.Hypertension25: 180\u2013185, 1995.","DOI":"10.1161\/01.HYP.25.2.180"},{"key":"REF55","doi-asserted-by":"crossref","unstructured":"Hisamoto K, Ohmichi M, Kurachi H, Hayakawa J, Kanda Y, Nishio Y, Adachi K, Tasaka K, Miyoshi E, Fujiwara N, Taniguchi N, and Murata Y.Estrogen induces the Akt-dependent activation of endothelial nitric-oxide synthase in vascular endothelial cells.J Biol Chem276: 3459\u20133467, 2001.","DOI":"10.1074\/jbc.M005036200"},{"key":"atypb1","doi-asserted-by":"crossref","unstructured":"Igarashi J, Bernier SG, and Michel T.Sphingosine 1-phosphate and activation of endothelial nitric-oxide synthase: differential regulation of Akt and MAP kinase pathways by EDG and bradykinin receptors in vascular endothelial cells.J Biol Chem276: 12420\u201312426, 2001.","DOI":"10.1074\/jbc.M008375200"},{"key":"REF57","doi-asserted-by":"crossref","unstructured":"Igarashi Jand Michel T.Sphingosine 1-phosphate and isoform-specific activation of phosphoinositide 3-kinase beta. Evidence for divergence and convergence of receptor-regulated endothelial nitric-oxide synthase signaling pathways.J Biol Chem276: 36281\u201336288, 2001.","DOI":"10.1074\/jbc.M105628200"},{"key":"REF58","doi-asserted-by":"crossref","unstructured":"Ignarro LJ, Buga GM, Wood KS, Byrns RE, and Chaudhuri G.Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.Proc Natl Acad Sci USA84: 9265\u20139269, 1987.","DOI":"10.1073\/pnas.84.24.9265"},{"key":"REF59","doi-asserted-by":"crossref","unstructured":"Ju H, Venema VJ, Marrero MB, and Venema RC.Inhibitory interactions of the bradykinin B2 receptor with endothelial nitric-oxide synthase.J Biol Chem273: 24025\u201324029, 1998.","DOI":"10.1074\/jbc.273.37.24025"},{"key":"REF60","doi-asserted-by":"crossref","unstructured":"Ju H, Zou R, Venema VJ, and Venema RC.Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity.J Biol Chem272: 18522\u201318525, 1997.","DOI":"10.1074\/jbc.272.30.18522"},{"key":"REF61","doi-asserted-by":"crossref","unstructured":"Kim YM, de Vera ME, Watkins SC, and Billiar TR.Nitric oxide protects cultured rat hepatocytes from tumor necrosis factor-alpha-induced apoptosis by inducing heat shock protein 70 expression.J Biol Chem272: 1402\u20131411, 1997.","DOI":"10.1074\/jbc.272.2.1402"},{"key":"REF62","doi-asserted-by":"crossref","unstructured":"Kou R, Greif D, and Michel T.Dephosphorylation of endothelial nitric-oxide synthase by vascular endothelial growth factor. Implications for the vascular responses to cyclosporin A.J Biol Chem277: 29669\u201329673, 2002.","DOI":"10.1074\/jbc.M204519200"},{"key":"REF63","doi-asserted-by":"crossref","unstructured":"Ku DN, Giddens DP, Zarins CK, and Glagov S.Pulsatile flow and atherosclerosis in the human carotid bifurcation. Positive correlation between plaque location and low oscillating shear stress.Arteriosclerosis5: 293\u2013302, 1985.","DOI":"10.1161\/01.ATV.5.3.293"},{"key":"REF64","doi-asserted-by":"crossref","unstructured":"Kuchan MJand Frangos JA.Role of calcium and calmodulin in flow-induced nitric oxide production in endothelial cells.Am J Physiol Cell Physiol266: C628\u2013C636, 1994.","DOI":"10.1152\/ajpcell.1994.266.3.C628"},{"key":"REF65","doi-asserted-by":"crossref","unstructured":"Kuchan MJ, Jo H, and Frangos JA.Role of G proteins in shear stress-mediated nitric oxide production by endothelial cells.Am J Physiol Cell Physiol267: C753\u2013C758, 1994.","DOI":"10.1152\/ajpcell.1994.267.3.C753"},{"key":"REF66","doi-asserted-by":"crossref","unstructured":"Lane Pand Gross SS.Disabling a C-terminal autoinhibitory control element in endothelial nitric-oxide synthase by phosphorylation provides a molecular explanation for activation of vascular NO synthesis by diverse physiological stimuli.J Biol Chem277: 19087\u201319094, 2002.","DOI":"10.1074\/jbc.M200258200"},{"key":"REF67","doi-asserted-by":"crossref","unstructured":"Li J, Billiar TR, Talanian RV, and Kim YM.Nitric oxide reversibly inhibits seven members of the caspase family via S-nitrosylation.Biochem Biophys Res Commun240: 419\u2013424, 1997.","DOI":"10.1006\/bbrc.1997.7672"},{"key":"REF68","doi-asserted-by":"crossref","unstructured":"Malek AM, Greene AL, and Izumo S.Regulation of endothelin 1 gene by fluid shear stress is transcriptionally mediated and independent of protein kinase C and cAMP.Proc Natl Acad Sci USA90: 5999\u20136003, 1993.","DOI":"10.1073\/pnas.90.13.5999"},{"key":"REF69","doi-asserted-by":"crossref","unstructured":"Marletta MA.Nitric oxide synthase: aspects concerning structure and catalysis.Cell78: 927\u2013930, 1994.","DOI":"10.1016\/0092-8674(94)90268-2"},{"key":"REF70","doi-asserted-by":"crossref","unstructured":"Marrero MB, Venema VJ, Ju H, He H, Liang H, Caldwell RB, and Venema RC.Endothelial nitric oxide synthase interactions with G-protein-coupled receptors.Biochem J343: 335\u2013340, 1999.","DOI":"10.1042\/bj3430335"},{"key":"REF71","doi-asserted-by":"crossref","unstructured":"McCabe TJ, Fulton D, Roman LJ, and Sessa WC.Enhanced electron flux and reduced calmodulin dissociation may explain \u201ccalcium-independent\u201d eNOS activation by phosphorylation.J Biol Chem275: 6123\u20136128, 2000.","DOI":"10.1074\/jbc.275.9.6123"},{"key":"REF72","doi-asserted-by":"crossref","unstructured":"Michel JB, Feron O, Sacks D, and Michel T.Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+-calmodulin and caveolin.J Biol Chem272: 15583\u201315586, 1997.","DOI":"10.1074\/jbc.272.25.15583"},{"key":"REF73","doi-asserted-by":"crossref","unstructured":"Michel Tand Feron O.Nitric oxide synthases: which, where, how, and why?J Clin Invest100: 2146\u20132152, 1997.","DOI":"10.1172\/JCI119750"},{"key":"REF74","doi-asserted-by":"crossref","unstructured":"Michell BJ, Chen Z, Tiganis T, Stapleton D, Katsis F, Power DA, Sim AT, and Kemp BE.Coordinated control of endothelial nitric-oxide synthase phosphorylation by protein kinase C and the cAMP-dependent protein kinase.J Biol Chem276: 17625\u201317628, 2001.","DOI":"10.1074\/jbc.C100122200"},{"key":"REF75","doi-asserted-by":"crossref","unstructured":"Michell BJ, Griffiths JE, Mitchelhill KI, Rodriguez-Crespo I, Tiganis T, Bozinovski S, de Montellano PR, Kemp BE, and Pearson RB.The Akt kinase signals directly to endothelial nitric oxide synthase.Curr Biol9: 845\u2013848, 1999.","DOI":"10.1016\/S0960-9822(99)80371-6"},{"key":"REF76","doi-asserted-by":"crossref","unstructured":"Michell BJ, Harris MB, Chen ZP, Ju H, Venema VJ, Blackstone MA, Huang W, Venema RC, and Kemp BE.Identification of regulatory sites of phosphorylation of the bovine endothelial nitric-oxide synthase at serine 617 and serine 635.J Biol Chem277: 42344\u201342351, 2002.","DOI":"10.1074\/jbc.M205144200"},{"key":"REF77","doi-asserted-by":"crossref","unstructured":"Mizuno K, Miyamoto A, Satomura K, Kurita A, Arai T, Sakurada M, Yanagida S, and Nakamura H.Angioscopic coronary macromorphology in patients with acute coronary disorders.Lancet337: 809\u2013812, 1991.","DOI":"10.1016\/0140-6736(91)92514-3"},{"key":"REF78","doi-asserted-by":"crossref","unstructured":"Morales-Ruiz M, Lee MJ, Zollner S, Gratton JP, Scotland R, Shiojima I, Walsh K, Hla T, and Sessa WC.Sphingosine 1-phosphate activates Akt, nitric oxide production, and chemotaxis through a Giprotein\/phosphoinositide 3-kinase pathway in endothelial cells.J Biol Chem276: 19672\u201319677, 2001.","DOI":"10.1074\/jbc.M009993200"},{"key":"REF79","doi-asserted-by":"crossref","unstructured":"Mugge A, Elwell JH, Peterson TE, Hofmeyer TG, Heistad DD, and Harrison DG.Chronic treatment with polyethyleneglycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits.Circ Res69: 1293\u20131300, 1991.","DOI":"10.1161\/01.RES.69.5.1293"},{"key":"REF80","doi-asserted-by":"crossref","unstructured":"Nishida CRand Ortiz de Montellano PR.Autoinhibition of endothelial nitric-oxide synthase. Identification of an electron transfer control element.J Biol Chem274: 14692\u201314698, 1999.","DOI":"10.1074\/jbc.274.21.14692"},{"key":"REF81","doi-asserted-by":"crossref","unstructured":"Nishida K, Harrison DG, Navas JP, Fisher AA, Dockery SP, Uematsu M, Nerem RM, Alexander RW, and Murphy TJ.Molecular cloning and characterization of the constitutive bovine aortic endothelial cell nitric oxide synthase.J Clin Invest90: 2092\u20132096, 1992.","DOI":"10.1172\/JCI116092"},{"key":"REF82","doi-asserted-by":"crossref","unstructured":"Niu J, Vaiskunaite R, Suzuki N, Kozasa T, Carr DW, Dulin N, and Voyno-Yasenetskaya TA.Interaction of heterotrimeric G13 protein with an A-kinase-anchoring protein 110 (AKAP110) mediates cAMP-independent PKA activation.Curr Biol11: 1686\u20131690, 2001.","DOI":"10.1016\/S0960-9822(01)00530-9"},{"key":"REF83","doi-asserted-by":"crossref","unstructured":"Ohara Y, Peterson TE, and Harrison DG.Hypercholesterolemia increases endothelial superoxide anion production.J Clin Invest91: 2546\u20132551, 1993.","DOI":"10.1172\/JCI116491"},{"key":"REF84","doi-asserted-by":"crossref","unstructured":"Ohno M, Gibbons GH, Dzau VJ, and Cooke JP.Shear stress elevates endothelial cGMP. Role of a potassium channel and G protein coupling.Circulation88: 193\u2013197, 1993.","DOI":"10.1161\/01.CIR.88.1.193"},{"key":"REF85","doi-asserted-by":"crossref","unstructured":"Palmer RM, Ferrige AG, and Moncada S.Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor.Nature327: 524\u2013526, 1987.","DOI":"10.1038\/327524a0"},{"key":"REF86","doi-asserted-by":"crossref","unstructured":"Pollock JS, Forstermann U, Mitchell JA, Warner TD, Schmidt HH, Nakane M, and Murad F.Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells.Proc Natl Acad Sci USA88: 10480\u201310484, 1991.","DOI":"10.1073\/pnas.88.23.10480"},{"key":"REF87","doi-asserted-by":"crossref","unstructured":"Pritchard KAJr, Ackerman AW, Gross ER, Stepp DW, Shi Y, Fontana JT, Baker JE, and Sessa WC.Heat shock protein 90 mediates the balance of nitric oxide and superoxide anion from endothelial nitric-oxide synthase.J Biol Chem276: 17621\u201317624, 2001.","DOI":"10.1074\/jbc.C100084200"},{"key":"REF88","doi-asserted-by":"crossref","unstructured":"Razani B, Rubin CS, and Lisanti MP.Regulation of cAMP-mediated signal transduction via interaction of caveolins with the catalytic subunit of protein kinase A.J Biol Chem274: 26353\u201326360, 1999.","DOI":"10.1074\/jbc.274.37.26353"},{"key":"REF89","doi-asserted-by":"crossref","unstructured":"Rizzo V, McIntosh DP, Oh P, and Schnitzer JE.In situ flow activates endothelial nitric oxide synthase in luminal caveolae of endothelium with rapid caveolin dissociation and calmodulin association.J Biol Chem273: 34724\u201334729, 1998.","DOI":"10.1074\/jbc.273.52.34724"},{"key":"REF90","doi-asserted-by":"crossref","unstructured":"Rossig L, Haendeler J, Hermann C, Malchow P, Urbich C, Zeiher AM, and Dimmeler S.Nitric oxide down-regulates MKP-3 mRNA levels: involvement in endothelial cell protection from apoptosis.J Biol Chem275: 25502\u201325507, 2000.","DOI":"10.1074\/jbc.M002283200"},{"key":"REF91","doi-asserted-by":"crossref","unstructured":"Schilling WP, Mo M, and Eskin SG.Effect of shear stress on cytosolic Ca2+of calf pulmonary artery endothelial cells.Exp Cell Res198: 31\u201335, 1992.","DOI":"10.1016\/0014-4827(92)90145-X"},{"key":"REF92","doi-asserted-by":"crossref","unstructured":"Shaul PW.Regulation of endothelial nitric oxide synthase: location, location, location.Annu Rev Physiol64: 749\u2013774, 2002.","DOI":"10.1146\/annurev.physiol.64.081501.155952"},{"key":"REF93","doi-asserted-by":"crossref","unstructured":"Sun Jand Liao JK.Functional interaction of endothelial nitric oxide synthase with a voltage-dependent anion channel.Proc Natl Acad Sci USA99: 13108\u201313113, 2002.","DOI":"10.1073\/pnas.202260999"},{"key":"REF94","doi-asserted-by":"crossref","unstructured":"Tanimoto T, Jin ZG, and Berk BC.Transactivation of VEGF receptor Flk-1\/KDR is involved in sphingosine 1-phosphate-stimulated phosphorylation of Akt and eNOS.J Biol Chem, 2002.","DOI":"10.1074\/jbc.M204764200"},{"key":"REF95","doi-asserted-by":"crossref","unstructured":"Thomas SR, Chen K, and Keaney JF Jr.Hydrogen peroxide activates endothelial nitric-oxide synthase through coordinated phosphorylation and dephosphorylation via a phosphoinositide 3-kinase-dependent signaling pathway.J Biol Chem277: 6017\u20136024, 2002.","DOI":"10.1074\/jbc.M109107200"},{"key":"REF96","doi-asserted-by":"crossref","unstructured":"Toker Aand Newton AC.Cellular signaling: pivoting around PDK-1.Cell103: 185\u2013188, 2000.","DOI":"10.1016\/S0092-8674(00)00110-0"},{"key":"REF97","doi-asserted-by":"crossref","unstructured":"Tsao PS, Buitrago R, Chan JR, and Cooke JP.Fluid flow inhibits endothelial adhesiveness. Nitric oxide and transcriptional regulation of VCAM-1.Circulation94: 1682\u20131689, 1996.","DOI":"10.1161\/01.CIR.94.7.1682"},{"key":"REF98","doi-asserted-by":"crossref","unstructured":"Tsao PS, Lewis NP, Alpert S, and Cooke JP.Exposure to shear stress alters endothelial adhesiveness. Role of nitric oxide.Circulation92: 3513\u20133519, 1995.","DOI":"10.1161\/01.CIR.92.12.3513"},{"key":"REF99","doi-asserted-by":"crossref","unstructured":"Venema RC, Sayegh HS, Kent JD, and Harrison DG.Identification, characterization, and comparison of the calmodulin-binding domains of the endothelial and inducible nitric oxide synthases.J Biol Chem271: 6435\u20136440, 1996.","DOI":"10.1074\/jbc.271.11.6435"},{"key":"REF100","doi-asserted-by":"crossref","unstructured":"Venema VJ, Marrero MB, and Venema RC.Bradykinin-stimulated protein tyrosine phosphorylation promotes endothelial nitric oxide synthase translocation to the cytoskeleton.Biochem Biophys Res Commun226: 703\u2013710, 1996.","DOI":"10.1006\/bbrc.1996.1417"},{"key":"REF101","doi-asserted-by":"crossref","unstructured":"Zou MH, Hou XY, Shi CM, Nagata D, Walsh K, and CohenRA.Modulation by peroxynitrite of Akt- and AMP-activated kinase-dependent serine phosphorylation of endothelial nitric oxide synthase.J Biol Chem277: 32552\u201332557, 2002.","DOI":"10.1074\/jbc.M204512200"}],"container-title":["American Journal of Physiology-Cell Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.physiology.org\/doi\/pdf\/10.1152\/ajpcell.00122.2003","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T09:53:56Z","timestamp":1746006836000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.physiology.org\/doi\/10.1152\/ajpcell.00122.2003"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,9]]},"references-count":101,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2003,9]]}},"alternative-id":["10.1152\/ajpcell.00122.2003"],"URL":"https:\/\/doi.org\/10.1152\/ajpcell.00122.2003","relation":{},"ISSN":["0363-6143","1522-1563"],"issn-type":[{"value":"0363-6143","type":"print"},{"value":"1522-1563","type":"electronic"}],"subject":[],"published":{"date-parts":[[2003,9]]}}}