Axl mediates vascular remodeling induced by deoxycorticosterone acetate-salt hypertension.
Axl, 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 Axl plays a significant role in vascular remodeling in response to injury. Here we investigated the role of Axl in the pathogenesis of hypertension in a deoxycorticosterone acetate (DOCA)-salt model. Hypertension was induced in Axl wild-type (Axl(+/+)) mice and Axl-deficient (Axl(-/-)) 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 Axl(+/+) DOCA, whereas systolic blood pressure levels in Axl(-/-) 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 Axl(+/+) DOCA mice compared with Axl(+/+) controls, whereas in Axl(-/-) DOCA mice relaxation responses were similar to Axl(-/-) controls. In addition, endothelium-independent vasorelaxation was improved in Axl(-/-) DOCA mice compared with Axl(+/+) DOCA mice. Nitrotyrosine and phospho-Akt immunoreactivity was significantly reduced in arteries from Axl(-/-) DOCA mice compared with Axl(+/+) DOCA mice. The remodeling index of the mesenteric artery (media:lumen ratio) was significantly increased in Axl(+/+) DOCA mice compared with Axl(-/-) DOCA mice. Finally, increased vascular apoptosis in the Axl(-/-) DOCA mice suggests a likely mechanism for Axl-dependent effects on hypertension. These data strengthen the pathogenic role for Axl in salt-sensitive hypertension.
Korshunov
Vyacheslav A
VA
Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester, NY 14642, USA. Slava_Korshunov@URMC.rochester.edu
Daul
Matthew
M
Massett
Michael P
MP
Berk
Bradford C
BC
D000818:Animals; D001011:Aorta / Q000503:physiopathology; D017209:Apoptosis; D001808:Blood Vessels / Q000473:pathology*; D003900:Desoxycorticosterone / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D008638:Mesenteric Arteries / Q000473:pathology; D051379:Mice; D015513:Oncogene Proteins / Q000502:physiology*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D012965:Sodium Chloride / Q000494:pharmacology*; D013599:Systole / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D000094963:Axl Receptor Tyrosine Kinase
D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; C000722290:AXL receptor tyrosine kinase, mouse