Insufficient angiogenesis is one of the causes leading to tissue ischemia and 
dysfunction. In heart failure, there is increasing evidence showing decreased 
capillary density in the left ventricle (LV) myocardium, although the detailed 
mechanisms contributing to it are not clear. The goal of this study was to 
investigate the role of thyroid hormone receptors (TRs) in the coronary 
microvascular rarefaction under pathological cardiac hypertrophy. The LV from 
hypertrophied/failing hearts induced by ascending aortic constriction (AAC) 
exhibited severe microvascular rarefaction, and this phenomenon was restored by 
chronic T(3) administration. Coronary endothelial cells (ECs) isolated from AAC 
hearts expressed lower TRbeta mRNA than control ECs, and chronic T(3) 
administration restored TRbeta mRNA expression level in AAC hearts to the 
control level. Among different TR subtype-specific knockout mice, TRbeta 
knockout and TRalpha/TRbeta double-knockout mice both exhibited significantly 
less capillary density in LV compared with wild-type mice. In vitro, coronary 
ECs isolated from TRbeta knockout mice lacked the ability to form capillary 
networks. In addition, we identified that kinase insert domain protein 
receptor/fetal liver kinase-1 (vascular endothelial growth factor-2 receptor) 
was one of the angiogenic mediators controlled by T(3) administration in the AAC 
heart. These data suggest that TRbeta in the coronary ECs regulates capillary 
density during cardiac development, and down-regulation of TRbeta results in 
coronary microvascular rarefaction during pathological hypertrophy.