Axl mediates vascular remodeling induced by deoxycorticosterone acetate-salt hypertension

Ax1, a receptor tyrosine kinase, was recently identified as a novel candidate gene in a genetic model of salt- sensitive hypertension (Sabra rat). Our group first reported that Ax1 plays a significant role in vascular remodeling in response to injury. Here we investigated the role of Ax1 in the pathogenesis of hypertension in a deoxycorticosterone acetate ( DOCA) - salt model. Hypertension was induced in Ax1 wild- type (Ax1(+/+)) mice and Ax1-deficient ( Ax1(-/-)) mice by uninephrectomy and DOCA- salt for 6 weeks. Controls were uninephrectomized and received tap water and regular chow ad libitum. DOCA-salt treatment increased systolic blood pressure by 25 mm Hg in both genotypes after 1 week. Systolic blood pressure remained significantly elevated in Ax1(+/+) DOCA, whereas systolic blood pressure levels in Ax1(-/-) DOCA mice were the same as controls at 6 weeks. DOCA-salt increased relative kidney weight and glomerular hypertrophy by 40% compared with controls in both genotypes. Consistent with levels of systolic blood pressure, endothelium- dependent vasorelaxation was impaired in Ax1(+/+) DOCA mice compared with Ax1(+/+) controls, whereas in Ax1(-/-) DOCA mice relaxation responses were similar to Ax1(-/-) controls. In addition, endothelium- independent vasorelaxation was improved in Ax1(-/-) DOCA mice compared with Ax1(+/+) DOCA mice. Nitrotyrosine and phospho- Akt immunoreactivity was significantly reduced in arteries from Ax1(-/-) DOCA mice compared with Ax1(+/+) DOCA mice. The remodeling index of the mesenteric artery ( media: lumen ratio) was significantly increased in Ax1(+/+) DOCA mice compared with Ax1(-/-) DOCA mice. Finally, increased vascular apoptosis in the Ax1(-/-) DOCA mice suggests a likely mechanism for Ax1-dependent effects on hypertension. These data strengthen the pathogenic role for Ax1 in salt-sensitive hypertension. ( Hypertension. 2007; 50: 1057- 1062.).