No direct involvement of Phactr-1 in non-atherosclerotic arteriopathies: results from 3 different Phactr-1 transgenic knockout mice

Abstract Introduction Genome-wide association studies have revealed robust associations of common genetic polymorphisms in the Phactr1 locus (6p24) (encoding Phosphatase and Actin Regulator 1) with cervico-cerebral artery dissection (CCeAD), spontaneous coronary artery dissection (SCAD) and fibromuscular dysplasia (FMD). These common elements of genetic predisposition provide a proof of concept for important shared mechanisms at the molecular level between CCeAD, SCAD and FMD vascular diseases. Objective Deciphering genetic, molecular and physiological importance of PHACTR1. Method Using various tissue-specific Cre-driver mouse lines, Phactr1 was deleted either in endothelial cells (EC) using 2 tissue-specific Cre-driver (one of them was embryonic) and Smooth Muscle Cells (SMC) with a third tissue-specific Cre-driver to assess its role in the pathogenesis of CCeAD, SCAD or FMD. Results To test the efficacy of the Phactr1 deletion after cre-induction, we confirmed firstly, a decrease in Phactr1 transcription and Phactr1 expression in EC and SMC isolated from Phactr1iPDGFB and Phactr1iSMA mice. Irrespective to the tissue or the duration of the deletion, mice did not spontaneously display pathological phenotype or vascular impairment: mouse survival, growth, blood pressure, large vessel morphology or actin organization were not different in KO mice than their comparatives littermates. Challenging vascular function and repair either by angiotensin-II-induced hypertension or limb ischemia did not lead to vascular morphology or function impairment in Phactr1-deleted mice. Similarly, there was no more consequences of Phactr1 deletion during embryogenesis in ECs. Conclusion Loss of function of PHACTR-1 in the cell types mostly involved in vascular physiology does not appear to induce a pathological vascular phenotype. Funding Acknowledgement Type of funding sources: None.