Question:

Remodeling of the blood vessel wall along with phenotype changes of its resident cells is a hallmark of hypertension-induced arterial remodeling. Although long term clinical consequences of this remodeling process are well known, very little is known about the molecular mechanism initiating it. In vitro studies have revealed a potentially important role of the mechnotransducer protein zyxin therein. Here we have analyzed the role of zyxin in hypertension-induced arterial remodeling in vivo.

Methods:

To this end, wild type (WT) and zyxin-deficient (KO) mice were made hypertensive with deoxycorticosterone acetate (DOCA)-salt treatment. Telemetric recordings in vivo, real time RT-PCR and immunofluorescence analyses ex vivo as well as in vitro migration, proliferation and gel compaction assays with aortic smooth muscle cells (SMCs) derived from these animals were performed.

Results:

DOCA-salt treatment induced a significant rise in systolic and diastolic blood pressure in WT mice but not KO mice after 21 days. Moreover, there was a profound increase in expression of genes controlling extracellular matrix composition and SMC proliferation in femoral arteries ex vivo. Further differences pertained to the expression of PCNA, calponin, tenascin C and collagen IV. In vitro, zyxin-deficient SMCs revealed a pro-migratory and growth-promoting but poorly contractile (i.e., synthetic) phenotype. These data are in line with our previous findings in femoral arteries of KO mice demonstrating reduced expression of receptors for vasoconstrictors and a very weak myogenic response.

Conclusion:

Collectively, our data suggest an important role of zyxin in hypertension-induced arterial remodeling turning it to a potential future therapeutic target.