Study of physiological angiogenesis and associated signalling mechanisms in 
adult heart has been limited by the lack of a robust animal model. We 
investigated thyroid hormone-induced sprouting angiogenesis and the underlying 
mechanism. Hypothyroidism was induced in C57BL/6J mice by feeding with 
propylthiouracil (PTU). One year of PTU treatment induced heart failure. Both 12 
weeks- (young) and 1 year-PTU (middle age) treatment caused a remarkable 
capillary rarefaction observed in capillary density. Three-day Triiodothyronine 
(T3) treatment significantly induced cardiac capillary growth in hypothyroid 
mice. In cultured left ventricle (LV) tissues from PTU-treated mice, T3 also 
induced robust sprouting angiogenesis where pericyte-wrapped endothelial cells 
formed tubes. The in vitro T3 angiogenic response was similar in mice 
pre-treated with PTU for periods ranging from 1.5 to 12 months. Besides bFGF and 
VEGF(164) , PDGF-BB was the most robust angiogenic growth factor, which 
stimulated notable sprouting angiogenesis in cultured hypothyroid LV tissues 
with increasing potency, but had little effect on tissues from euthyroid mice. 
T3 treatment significantly increased PDGF receptor beta (PDGFR-β) protein levels 
in hypothyroid heart. PDGFR inhibitors blocked the action of T3 both on 
sprouting angiogenesis in cultured LV tissue and on capillary growth in vivo. In 
addition, activation of Akt signalling mediated in T3-induced angiogenesis was 
blocked by PDGFR inhibitor and neutralizing antibody. Our results suggest that 
hypothyroidism leads to cardiac microvascular impairment and rarefaction with 
increased sensitivity to angiogenic growth factors. T3-induced cardiac sprouting 
angiogenesis in adult hypothyroid mice was associated with PDGF-BB, PDGFR-β and 
downstream activation of Akt.