CTP synthase, a smooth muscle‐sensitive therapeutic target for effective vascular repair after injury

Abstract

Neointima formation due to smooth muscle cell (SMC) proliferation following injury is a major medical challenge in cardiovascular intervention. However, anti–neointimal drugs often block re‐endothelialization as a side effect. Identification of SMC sensitive therapeutic targets will potentially conquer this medical barrier. In the present study, we identified CTP synthase (CTPS) as one of these potential targets. Blockade of CTPS function by shRNA or its specific inhibitor suppressed SMC proliferation and neointima formation. In contrast, targeting CTPS treatments had no side effects on endothelial cell (EC) in vitro, and promoted reendothelialization in vivo. Mechanistically, blockade of CTPS pathway activated CTP synthesis salvage pathway in ECs but not in SMCs, which sustained EC proliferation. Meanwhile, blockade of CTPS function induced SMC phenotypic modulation into the contractile phenotype, which characterized by the expression of pro‐angiogenic factors while inhibiting anti‐angiogenic factors in SMCs, leading to enhanced EC proliferation. In summary, for the first time, our study discovered a fundamental difference between SMC and EC in their CTP biosynthesis during pathological proliferation which provided a novel strategy to selectively block SMC proliferation while not disturbing or even promoting reendothelialization for effective vascular repair after injury.