Effects of thyroidectomy, T₄, and DITPA replacement on brain blood vessel density in adult rats

Abstract

Schlenker EH, Hora M, Liu Y, Redetzke RA, Morkin E, Gerdes AM. Effects of thyroidectomy, T4, and DITPA replacement on brain blood vessel density in adult rats. Am J Physiol Regul Integr Comp Physiol 294: R1504-R1509, 2008. First published March 19, 2008 doi:10.1152/ajpregu.00027.2008.-In hypothyroid patients, altered microvascular structure and function may affect mood and cognitive function. We hypothesized that adult male hypothyroid rats will have significantly lower forebrain blood vessel densities (BVD) than euthyroid rats and that treatment with 3,5-diiothyroprionic acid (DITPA) (a thyroid hormone analog) or thyroxine (T4) will normalize BVDs. The euthyroid group received no thyroidectomy or treatment. The other three groups received thyroidectomies and pellets. The hypothyroid group received a placebo pellet, the DITPA group received an 80-mg DITPA-containing pellet, and the T4 group received a 5.2-mg T4 slow-release pellet for 6 wk. Body weights, cardiac function, and body temperatures were measured. A monoclonal antiplatelet endothelial cell adhesion antibody was used to visualize blood vessels. The euthyroid group averaged body weights of 548 Ϯ 54 g, while the hypothyroid group averaged a body weight of 332 Ϯ 19 g (P value Ͻ 0.001). Relative to the euthyroid group, the DITPA-treated group was significantly lighter (P value Ͻ 0.05), while the T4-treated group was comparable in body weight to the euthyroid group. The same trends were seen with body temperature and cardiac function with the largest difference between the euthyroid and hypothyroid groups. BVD in the euthyroid group was 147 Ϯ 12 blood vessels/mm 2 and in hypothyroid group 69 Ϯ 5 blood vessels/mm 2 (P ϭ 0.013) but similar among the euthyroid, DITPA, and T4 groups. These results show that hypothyroidism decreased BVD in adult rat forebrain regions. Moreover, DITPA and T4 were efficacious in preventing effects of hypothyroidism on cardiac function and BVD.hypothyroid; angiogenesis; echocardiography; thyroid hormones HYPOTHYROIDISM IS A RELATIVELY common disorder affecting ϳ5% of adults and 15% of older women (2, 10). Consequences of hypothyroidism in adults include fatigue, cold intolerance, exertion, cognitive and mood dysfunction, decreased body temperature, elevated levels of triglycerides and cholesterol, hoarseness, sleep apnea, and cardiovascular dysfunction (2,14,29). Although less investigated, hypothyroidism may also decrease blood vessel density, which in turn decreases delivery of oxygen and nutrients to tissues. Since hypothyroidism may depress ventilation, leading to hypoxemia (26), the consequences of decreased blood vessel density could be enhanced in hypothyroid patients who have cardiac disease or suffer from sleep apnea and exacerbate altered cognition, mood disturbances, and fatigue.Thyroid hormone supplementation directly affects the cardiovascular system to increase cardiac contractile function and hypertrophy, as well as cause vasodilatation (17). Recent studies indicate that thyroid supplementation also may increase blo...

Thyroid hormone analog 3,5-diiodothyropropionic acid promotes healthy vasculature in the adult myocardium independent of thyroid effects on cardiac function

“…Minor modifications in structure may alter the efficiency of thyroid analog uptake (6), TH receptor binding (14), or recruitment of coactivators or corepressors (33). Our previous study and the current one indicate that DITPA can be administered at a dose which promotes a healthy vasculature in the brain and heart with limited metabolic effects (25). It would be helpful to determine the angiogenic properties of other available thyroid analogs to better understand their potential therapeutic utility.…”

“…DITPA can also induce angiogenesis and arteriolar growth in postinfarcted myocardium (31,35) and increase the protein expression of vascular endothelial growth factor (VEGF) 164 , VEGF 188 , basic fibroblast growth factor (bFGF or FGF-2), angiopoietin-1, and Tie-2 (32). Our previous studies also demonstrated that DITPA administration increased myocardial blood flow in BIO-TO2 cardiomyopathic hamsters (13) and prevented the loss of brain blood vessels in rats as they developed hypothyroidism (25). However, phase-2 clinical trials conducted by the Department of Veterans Affairs and Titan Pharmaceuticals, in the management of patients with New York Health Association class III and IV heart failure, were terminated recently due to body mass loss, although this occurred in overweight rather than normal-weight individuals (clinicaltrials.gov).…”

Thyroid hormone induced angiogenesis through the integrin αvβ3/protein kinase D/histone deacetylase 5 signaling pathway

“…Schlenker et al (2008) reported that hypothyroidism in rats induces a decrease in brain blood vessel density. Replacement with 3,5-diiothyroprionic acid and T 4 effectively prevented the effects of hypothyroidism on cardiac function and increased blood vessel density.…”

Translational implications of nongenomic actions of thyroid hormone initiated at its integrin receptor

“…Kuzman and colleagues (28,29) have shown that agonist thyroid hormone (thyromimetic) analogs are proangiogenic in the postinfarcted hamster heart by a pathway that involves Akt signaling. Thyroid hormone also has substantial proangiogenic activity on brain blood vessels (57). Angiogenic activity of iodothyronine analogs that is initiated at the integrin receptor has been demonstrated in the blood vessels of the chick chorioallantoic membrane (CAM) model (11,45,47) and the human dermal microvascular endothelial cell (HDMEC) sprouting model (46).…”