Antenatal/early postnatal hypothyroidism alters arterial tone regulation in 2-week-old rats

Abstract

The mechanisms of vascular alterations resulting from early thyroid hormones deficiency are poorly understood. We tested the hypothesis that antenatal/early postnatal hypothyroidism would alter the activity of endothelial NO pathway and Rho-kinase pathway, which are specific for developing vasculature. Dams were treated with propylthiouracil (PTU, 7 ppm) in drinking water during gestation and 2 weeks after delivery, and their progeny had normal body weight but markedly reduced blood levels of thyroid hormones (ELISA). Small arteries from 2-week-old male pups were studied using wire myography, qPCR and Western blotting. Mesenteric arteries of PTU pups, compared to controls, demonstrated smaller maximum response to α-adrenergic agonist methoxamine and reduced mRNA contents of smooth muscle differentiation markers α-actin and SERCA2A. Inhibition of basal NO synthesis by l-NNA led to tonic contraction of mesenteric arteries and augmented their contractile responses to methoxamine; both l-NNA effects were impaired in PTU pups. PTU pups demonstrated lower blood level of NO metabolites compared to control group (Griess reaction). Rho-kinase inhibitor Y27632 strongly reduced mesenteric arteries responses to methoxamine in PTU pups, that was accompanied by elevated Rho-kinase content in their arteries in comparison to control ones. Unlike mesenteric, saphenous arteries of PTU pups, compared to controls, had no changes in α-actin and SERCA2A contents and in responses to l-NNA and Y27632. In conclusion, thyroid hormones deficiency suppresses the anticontractile effect of NO and potentiates the procontractile Rho-kinase effects in mesenteric arteries of 2-week-old pups. Such alterations disturb perinatal cardiovascular homeostasis and might lead to cardiovascular pathologies in adulthood.

Antenatal/early postnatal hypothyroidism increases the contribution of Rho-kinase to contractile responses of mesenteric and skeletal muscle arteries in adult rats

“…Thyroid state is completely restored in adult rats suffered from antenatal/early postnatal hypothyroidism The results of the present study are consistent with our previous findings and show that treatment of dams with relatively low PTU dosage (7 ppm) causes significant reduction of thyroid hormones concentrations in their 2-week-old progeny, which, however, restores to adulthood. 9,10 Of note, already at the age of 6 weeks, the progeny of PTU-treated dams demonstrated restored blood levels of thyroid hormones and TSH, 20 which is consistent with other studies, where the restoration of thyroid state was observed in 4 weeks after PTU withdrawal. 8 Based on the above, we can consider that the adult rats from PTU group had an euthyroid status for at least 4 weeks before their arteries were taken for in vitro studies.…”

“…Maximum contractility is not changed in adult rats, suffered from antenatal/early postnatal hypothyroidism Noteworthy, at the age of 2 weeks the maximum active force of arteries was significantly reduced by antenatal/early postnatal hypothyroidism, along with reduced mRNA contents of smooth muscle differentiation markers, such as, smooth muscle MHC, αactin, and SERCA2A. 10 These data point to the retardation of arterial development by maternal thyroid deficiency. However, the intergroup difference in the maximum active force disappeared by the age of 10-12 weeks, suggesting unaltered contents of contractile proteins in arteries of previously hypothyroid rats.…”

“…9 Further, antenatal/early postnatal hypothyroidism did not affect the responses of saphenous (cutaneous) artery but suppressed the activity of NO-pathway and increased procontractile effects of Rho-kinase in small mesenteric arteries of 2-week-old rat pups. 10 Importantly, our study 10 was the first to demonstrate the functional link between thyroid hormones and Rho-kinase pathway, a key regulator of smooth muscle contraction in vascular system. Rho-kinase substantially increases the sensitivity of contractile apparatus to Ca 2+ downstream to activation of membrane receptors, 11 e.g., α 1 -adrenоceptors.…”

“…The model of antenatal/early postnatal hypothyroidism Detailed description of our maternal hypothyroidism model was provided recently. 10 Briefly, pregnant dams were randomly divided into two groups. One group (n = 5) was treated with 6propyl-2-thiouracil in the drinking water (PTU, 7 ppm or 0.0007%, w/v, Sigma) from the first gestational day until 14 th day after delivery.…”

“…We chose to follow up on saphenous and mesenteric arteries in adult rats, as these arteries have been already studied in 2-week-old pups. 10 Additionally, we studied sural (gastrocnemius muscle) artery, since skeletal muscles and their blood supply demonstrate clear insufficiencies in hypothyroid animals 17 , but possible role of Rhokinase in such alterations was not addressed in previous studies.…”