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.

Deciphering genetic, molecular and physiological importance of PHACTR1.

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.

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 Phactr1^iPDGFB and Phactr1^iSMA 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.

Loss of function of PHACTR-1 in the cell types mostly involved in vascular physiology does not appear to induce a pathological vascular phenotype.