DITPA stimulates bFGF, VEGF, angiopoietin, and Tie-2 and facilitates coronary arteriolar growth

Abstract

.-Previous studies from our laboratory and those of others have shown thyroxine to be a stimulator of coronary microvascular growth. The present study tested the hypothesis that 3,5-diiodothyropropionic acid (DITPA), a thyroid hormone analog with inotropic but not chronotopic characteristics, is angiogenic in the nonischemic heart. Daily injections (3.75 mg/kg sc) of DITPA to Sprague-Dawley rats affected protein increases in vascular endothelial growth factor (VEGF)164, VEGF188, basic fibroblast growth factor (bFGF) (FGF-2), angiopoietin-1, and Tie-2 during the first few days of treatment. After 3 wk of treatment, arteriolar length density and the relative number of terminal arterioles (Ͻ10 m diameter) increased in the left ventricle as determined by image analysis of perfuse-fixed hearts. These findings occurred in hearts that did not undergo changes in mass nor in increases in capillary length density. We conclude that DITPA, which is known to improve ventricular function after infarction, is angiogenic in normal nonischemic hearts. growth factors; angiogenesis; 3,5-diiodothyroproprionic acid; basic fibroblast growth factor; vascular endothelial growth factor CORONARY ANGIOGENESIS during prenatal and postnatal growth is a well-established phenomenon. However, in the nonischemic adult heart, angiogenesis may or may not occur when the heart enlarges. Although some significant vascular growth may occur in certain animal models of hypertension (reviewed in Ref. 28), in patients with long-term left ventricular (LV) hypertrophy due to aortic stenosis, coronary reserve is usually markedly depressed even in the absence of coronary artery disease (5). In contrast, when hypertrophy occurs in response to volume overload, capillary and arteriolar growth are usually proportional to the magnitude of hypertrophy, and maximal coronary perfusion is maintained (2, 28). These findings support the concept that the stimulus evoking the hypertrophy is a determinant of angiogenesis. Perhaps the best example supporting this concept is thyroid hormone-induced hypertrophy, which is associated with a rapid and marked capillary growth (1,3,7,14,(24)(25)(26)30). Moreover, we have documented a normal maximal myocardial perfusion in rat hearts in which hypertrophy was induced with thyroxine, a finding that indicates compensatory growth of resistance vessels as well (25).In a previous study, we showed that 3,5-diiodothyropropionic acid (DITPA), a thyroxine analog, stimulates modest, early growth of the capillary bed in the myocardium surviving infarction (29). This agent has been shown to attenuate symptoms of heart failure after myocardial infarction through its positive inotropic effects (13,15,21). The favorable changes with DITPA treatment of rats or rabbits following coronary artery ligation and infarction include increased maximal positive and negative pressure development over time (dP/dt), increased basal time constant of isovolumic relaxation, and increased circumferential shortening and restoration of repolarizing transient outward...

Treatment of subclinical hypothyroidism reverses ischemia and prevents myocyte loss and progressive LV dysfunction in hamsters with dilated cardiomyopathy

“…Several studies have shown that thyroxine and the TH analog 3,5-diiodothyropropionic acid (DITPA) stimulate angiogenesis and increase baseline and maximum myocardial blood flow (4,9,(32)(33)(34)38). Another study by Heron and Raksuan (13) showed that neonatal hypothyroidism led to a reduction in myocardial arterioles.…”

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

“…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).…”

Influence of thyroid state on cardiac and renal capillary density and glomerular morphology in rats

“…Although TH and analogues are pro-angiogenic in various models, as reported earlier, their effects at the microvascular level remain controversial, with reports of unchanged (Wachtlova et al 1985, Breisch et al 1989, Heron & Rakusan 1994 or even reduced (Gerdes et al 1979, Weiss & Grover 1987, Tomanek et al 1995, Anjos-Ramos et al 2006 cardiac capillary density in hyperthyroid rats. Cardiac capillary density was found to be increased in hypothyroid rats (Heron & Rakusan 1994) and rabbits (Tomanek et al 1993).…”