Persistent insulin signaling coupled with restricted PI3K activation causes insulin-induced vasoconstriction

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Olver, T. Dylan ^[1] ; Grunewald, I, Zachary ; Ghiarone, Thaysa ^[2] ; Restaino, Robert M. ^{[2, 3]} ; Sales, Allan R. K. ^{[4, 2, 5]} ; Park, Lauren K. ^{[6, 2]} ; Thorne, Pamela K. ^[7] ; Ganga, Rama Rao ^[8] ; Emter, Craig A. ^[7] ; Lemon, Peter W. R. ^[9] ; Shoemaker, J. Kevin ^[9] ; Manrique-Acevedo, Camila ^{[2, 10, 11]} ; Martinez-Lemus, Luis A. ^{[2, 12]} ; Padilla, Jaume ^{[6, 2]}

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^[1] Univ Saskatchewan, Western Coll Vet Med, Dept Biomed Sci, Saskatoon, SK - Canada

^[2] Grunewald, Zachary, I, Univ Missouri, Dalton Cardiovasc Res Ctr, Columbia, MO 65211 - USA

^[3] Skidmore Coll, Dept Hlth & Human Physiol Sci, New York, NY - USA

^[4] Univ Sao Paulo, Heart Inst InCor, Med Sch, Sao Paulo - Brazil

^[5] Dor Inst Res & Educ, Sao Paulo - Brazil

^[6] Grunewald, Zachary, I, Univ Missouri, Dept Nutr & Exercise Physiol, Columbia, MO 65211 - USA

^[7] Univ Missouri, Dept Biomed Sci, Columbia, MO 65211 - USA

^[8] Univ Missouri, Dept Surg, Columbia, MO 65211 - USA

^[9] Univ Western Ontario, Sch Kinesiol, London, ON - Canada

^[10] Univ Missouri, Dept Med, Div Endocrinol Diabet & Metab, Columbia, MO 65211 - USA

^[11] Harry S Truman Mem Vet Hosp, Res Serv, Columbia, MO 65201 - USA

^[12] Univ Missouri, Dept Med Pharmacol & Physiol, Columbia, MO 65211 - USA

• Tipo de documento: Artigo Científico
• Fonte: AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY; v. 317, n. 5, p. H1166-H1172, NOV 2019.
• Citações Web of Science: 0

Resumo

Insulin modulates vasomotor tone through vasodilator and vasoconstrictor signaling pathways. The purpose of the present work was to determine whether insulin-stimulated vasoconstriction is a pathophysiological phenomenon that can result from a combination of persistent insulin signaling, suppressed phosphatidylinositol-3 kinase (PI3K) activation, and an ensuing relative increase in MAPK/endothelin-1 (ET-1) activity. First, we examined previously published work from our group where we assessed changes in lower-limb blood flow in response to an oral glucose tolerance test (endogenous insulin stimulation) in lean and obese subjects. The new analyses showed that the peak rise in vascular resistance during the postprandial state was greater in obese compared with lean subjects. We next extended on these findings by demonstrating that insulin-induced vasoconstriction in isolated resistance arteries from obese subjects was attenuated with ET-1 receptor antagonism, thus implicating ET-1 signaling in this constriction response. Last, we examined in isolated resistance arteries from pigs the dual roles of persistent insulin signaling and blunted PI3K activation in modulating vasomotor responses to insulin. We found that prolonged insulin stimulation did not alter vasomotor responses to insulin when insulin-signaling pathways remained unrestricted. However, prolonged insulin-ization along with pharmacological suppression of PI3K activity resulted in insulin-induced vasoconstriction, rather than vasodilation. Notably, such aberrant vascular response was rescued with either MAPK inhibition or ET-1 receptor antagonism. In summary. we demonstrate that insulin-induced vasoconstriction is a pathophysiological phenomenon that can be recapitulated when sustained insulin signaling is coupled with depressed PI3K activation and the concomitant relative increase in MAPK/ET-1 activity. NEW \& NOTEWORTHY This study reveals that insulin-induced vasoconstriction is a pathophysiological phenomenon. We also provide evidence that in the setting of persistent insulin signaling. impaired phosphatidylinositol-3 kinase activation appears to be a requisite feature precipitating MAPK/endothelin 1-dependent insulin-induced vasoconstriction. (AU)

• Processo FAPESP: 17/25613-6 - Exercício aeróbico habitual diminui endotelina 1 e restaura a vasodilatação induzida por insulina em pacientes com diabetes tipo 2: o papel do shear stress
• Beneficiário: Allan Robson Kluser Sales
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado