Hypertension is a complex disorder that involves multiple organ systems. Even though the role of immune cells (e.g., macrophages and T lymphocytes) is well accepted in hypertension, the underlying mechanisms are not completely understood. Our major hypothesis is that immune response in hypertension depends on a continuous interaction between immune-activated vascular cells, innate and adaptive immunity. Survival is very important for vascular cells in hypertension. We recently confirmed the pathogenic role for Axl, a receptor tyrosine kinase, on vascular dysfunction in the late phase of salt-sensitive hypertension. Axl-dependent pathways protect hypertensive vasculature from apoptosis. Preliminary data support our working hypothesis that Axl is a key regulator of the immune response in hypertension. We propose three specific aims to test the hypothesis and dissect mechanisms by which Axl regulates the immune response in hypertension. First, we will determine Axl-dependent effects on modulation of immune activation of vascular cells in hypertension. Second, we will identify innate immune cell types that are engaged in Axl-dependent vascular dysfunction in hypertension. Third, we will investigate the regulatory role of Axl in adaptive immunity (CD4 T lymphocytes) that maintains vascular dysfunction in hypertension. Our studies will provide new insights into the pathological mechanisms that regulate vascular dysfunction in hypertension. In particular, we will refine the current concept of the immune response in hypertension and emphasize the importance of retention (via survival) of immune cells in the artery wall at the later phases of hypertension. Finally, Axl-dependent molecular mechanisms can offer a novel therapeutic target for the treatment of hypertension.

Public Health Relevance

This proposal will refine the current concept of vascular dysfunction in hypertension and emphasize the importance of the immune mechanisms in later phases of hypertension. These data will set a strong base for development of original diagnostic tools and/or therapeutic target(s) to treat hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105623-04
Application #
8606490
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Maric-Bilkan, Christine
Project Start
2011-02-15
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
4
Fiscal Year
2014
Total Cost
$278,100
Indirect Cost
$98,100
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Smolock, Elaine M; Burke, Ryan M; Wang, Chenjing et al. (2014) Intima modifier locus 2 controls endothelial cell activation and vascular permeability. Physiol Genomics 46:624-33
Batchu, Sri N; Hughson, Angie; Gerloff, Janice et al. (2013) Role of Axl in early kidney inflammation and progression of salt-dependent hypertension. Hypertension 62:302-9
Batchu, Sri N; Korshunov, Vyacheslav A (2012) Novel tyrosine kinase signaling pathways: implications in vascular remodeling. Curr Opin Nephrol Hypertens 21:122-7
Gerloff, Janice; Korshunov, Vyacheslav A (2012) Immune modulation of vascular resident cells by Axl orchestrates carotid intima-media thickening. Am J Pathol 180:2134-43
Korshunov, Vyacheslav A (2012) Axl-dependent signalling: a clinical update. Clin Sci (Lond) 122:361-8