Protection from angiotensin II–mediated vasculotoxic and hypertensive response in mice lacking PI3Kγ

• DOI: 10.1084/jem.20040995
• Publication Date: 2005-04-12T00:23:47Z
• Authors: Carmine Vecchione; Enrico Patrucco; Gennaro Marino; Laura Barberis; Roberta Poulet; Alessandra Aretini; Angelo Maffei; Maria Teresa Gentile; Marianna Storto; Ornella Azzolino; Mara Brancaccio; Gian Luca Colussi; Umberto Bettarini; Fiorella Altruda; Lorenzo Silengo; Guido Tarone; Mathias P. Wymann; Emilio Hirsch; Giuseppe Lembo
• Keywords: Male; Mice, Knockout; 0301 basic medicine; Angiotensin II; hypertension; angiotensin; signal transduction; genetically modified mice; Article; Muscle, Smooth, Vascular; Mesenteric Arteries; 3. Good health; Isoenzymes; Mice; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Vasoconstriction; Hypertension; Animals; Vasoconstrictor Agents; Calcium; Reactive Oxygen Species; Angiotensin II; Animals; Aorta; Calcium; Cells, Cultured; Hypertension; Isoenzymes; Male; Mesenteric Arteries; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Phosphatidylinositol 3-Kinases; Reactive Oxygen Species; Vasoconstriction; Vasoconstrictor Agents; Immunology and Allergy; Immunology; Aorta; Cells, Cultured; Phosphoinositide-3 Kinase Inhibitors

Hypertension affects nearly 20% of the population in Western countries and strongly increases the risk for cardiovascular diseases. In the pathogenesis of hypertension, the vasoactive peptide of the renin-angiotensin system, angiotensin II and its G protein–coupled receptors (GPCRs), play a crucial role by eliciting reactive oxygen species (ROS) and mediating vessel contractility. Here we show that mice lacking the GPCR-activated phosphoinositide 3-kinase (PI3K)γ are protected from hypertension that is induced by administration of angiotensin II in vivo. PI3Kγ was found to play a role in angiotensin II–evoked smooth muscle contraction in two crucial, distinct signaling pathways. In response to angiotensin II, PI3Kγ was required for the activation of Rac and the subsequent triggering of ROS production. Conversely, PI3Kγ was necessary to activate protein kinase B/Akt, which, in turn, enhanced L-type Ca2+ channel–mediated extracellular Ca2+ entry. These data indicate that PI3Kγ is a key transducer of the intracellular signals that are evoked by angiotensin II and suggest that blocking PI3Kγ function might be exploited to improve therapeutic intervention on hypertension.