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.
Highlights
Thyroid diseases, which are estimated to affect 10% of the population [1,2] are accompanied by profound cardiovascular changes
The novel finding of the current study was that AT2R present in vascular smooth muscle cell (VSMC) plays a key role in the hyperthyroidism-induced decrease in contractile response accompanied by an increase in Akt/nitric oxide (NO) pathway signaling
This is based on the following results: a) Decreased contractile response to angiotensin II (AngII) in denuded aortas from hyperthyroid rats was attenuated by AT2R blocker; b) Decreased vascular contraction during hyperthyroidism was associated with increased levels of NO and activation of PI3K/Akt, both of which were attenuated through use of an AT2R blocker
Summary
Thyroid diseases, which are estimated to affect 10% of the population [1,2] are accompanied by profound cardiovascular changes. Hyperthyroidism induces a high-output state, with a marked decrease (up to a 50 percent) in systemic vascular resistance (SVR), possibly due to local release of vasodilators in peripheral tissues as a consequence of the elevated tissue metabolism [3]. The diminished SVR seen in hyperthyroidism has been attributed to a direct effect of T3, the biologically active form of thyroid hormone, on vascular endothelium [4]. Our group has demonstrated that T3 promoted marked NO production in VSMC by rapid nongenomic actions, which in turn contributed to vascular relaxation [5], suggesting the VSMC as a specific target of T3, which may represent an important factor for local control of vascular function. Several lines of evidence suggest an important contribution of the renin-angiotensin system (RAS) to the actions of the thyroid hormones (TH) [6,7,8,9]. AT2R promotes relaxation in rat isolated resistance arteries and aortas [16,17] via activation of a vasodilatory cascade involving bradykinin (BK), nitric oxide (NO), and guanosine cyclic 39,59-monophosphate (cGMP), counteracting AT1R-induced contraction [18,19]
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