Abstract
Coronary flow (CF) measured ex vivo is largely determined by capillary density that reflects angiogenic vessel formation in the heart in vivo. Here we exploit this relationship and show that CF in the rat is influenced by a locus on rat chromosome 2 that is also associated with cardiac capillary density. Mitochondrial tryptophanyl-tRNA synthetase (Wars2), encoding an L53F protein variant within the ATP-binding motif, is prioritized as the candidate at the locus by integrating genomic data sets. WARS2(L53F) has low enzyme activity and inhibition of WARS2 in endothelial cells reduces angiogenesis. In the zebrafish, inhibition of wars2 results in trunk vessel deficiencies, disordered endocardial-myocardial contact and impaired heart function. Inhibition of Wars2 in the rat causes cardiac angiogenesis defects and diminished cardiac capillary density. Our data demonstrate a pro-angiogenic function for Wars2 both within and outside the heart that may have translational relevance given the association of WARS2 with common human diseases.
Highlights
Coronary flow (CF) measured ex vivo is largely determined by capillary density that reflects angiogenic vessel formation in the heart in vivo
The rat is an excellent model of human cardiovascular physiology[14,15] and CF has been determined in a large number of rat strains with the Brown Norway (BN) rat having the highest CF of all rat strains (Supplementary Fig. 1)
On the basis of these data, we hypothesized that CF in the rat is under genetic control as it is in humans[7], and set out to dissect the genetic determinants underlying CF in a genetic intercross between the Spontaneously Hypertensive Rat (SHR) and the BN rat
Summary
Coronary flow (CF) measured ex vivo is largely determined by capillary density that reflects angiogenic vessel formation in the heart in vivo. We exploit this relationship and show that CF in the rat is influenced by a locus on rat chromosome 2 that is associated with cardiac capillary density. One of the most important pro-angiogenic signals is provided by vascular endothelial growth factor (VEGF), which activates quiescent endothelial cells (ECs) and promotes new vessel formation. The limitations of effective ways to regulate angiogenesis relate, in part, to our incomplete understanding of the underlying biology that we postulated, may be improved through genetic studies of CF in the ex vivo rat heart, which provides a model for an indirect, quantitative measurement of capillary density and, by inference, angiogenesis. Our findings describe a novel gene for angiogenesis both within and outside the heart
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