title: Emerging role of angiotensin type 2 receptor (AT2R)/Akt/NO pathway in vascular smooth muscle cell in the hyperthyroidism.
abstract: Hyperthyroidism is characterized by increased vascular relaxation and decreased vascular contraction and is associated with augmented levels of triiodothyronine (T3) that contribute to the diminished systemic vascular resistance found in this condition. T3 leads to augmented NO production via PI3K/Akt signaling pathway, which in turn causes vascular smooth muscle cell (VSMC) relaxation; however, the underlying mechanisms involved remain largely unknown. Evidence from human and animal studies demonstrates that the renin-angiotensin system (RAS) plays a crucial role in vascular function and also mediates some of cardiovascular effects found during hyperthyroidism. Thus, in this study, we hypothesized that type 2 angiotensin II receptor (AT2R), a key component of RAS vasodilatory actions, mediates T3 induced-decreased vascular contraction. Marked induction of AT2R expression was observed in aortas from T3-induced hyperthyroid rats (Hyper). These vessels showed decreased protein levels of the contractile apparatus: α-actin, calponin and phosphorylated myosin light chain (p-MLC). Vascular reactivity studies showed that denuded aortic rings from Hyper rats exhibited decreased maximal contractile response to angiotensin II (AngII), which was attenuated in aortic rings pre-incubated with an AT2R blocker. Further study showed that cultured VSMC stimulated with T3 (0.1 µmol/L) for 24 hours had increased AT2R gene and protein expression. Augmented NO levels and decreased p-MLC levels were found in VSMC stimulated with T3, both of which were reversed by a PI3K/Akt inhibitor and AT2R blocker. These findings indicate for the first time that the AT2R/Akt/NO pathway contributes to decreased contractile responses in rat aorta, promoted by T3, and this mechanism is independent from the endothelium.
authors: Laboratory of Cell Biology and Functional Anatomy, Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors: Maria Alícia
authors: MA
authors: Carrillo-Sepúlveda
authors: Graziela S
authors: GS
authors: Ceravolo
authors: Cristina R
authors: CR
authors: Furstenau
authors: Priscilla de Souza
authors: Pde S
authors: Monteiro
authors: Zuleica
authors: Z
authors: Bruno-Fortes
authors: Maria Helena
authors: MH
authors: Carvalho
authors: Francisco R
authors: FR
authors: Laurindo
authors: Rita C
authors: RC
authors: Tostes
authors: R Clinton
authors: RC
authors: Webb
authors: Maria Luiza M
authors: ML
authors: Barreto-Chaves
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006980:Hyperthyroidism / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014284:Triiodothyronine / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D044139:Receptor, Angiotensin, Type 2; D014284:Triiodothyronine; D000804:Angiotensin II; D009569:Nitric Oxide; D051057:Proto-Oncogene Proteins c-akt
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