Abstract 347: Chronic Kidney Disease Modulates Vascular Smooth Muscle Cell Phenotype and Increases de Novo Venous Intimal Hyperplasia
Background: Vascular access dysfunction associated with arteriovenous grafts and fistulas contributes significantly to the morbidity and mortality of end-stage renal disease (ESRD) patients receiving hemodialysis. The mechanism involved in the development of peri-anastomotic intimal hyperplasia, a major cause of the arteriovenous access dysfunction, is poorly elucidated. We hypothesized that the uremic condition associated with ESRD promotes a pathophysiological vascular smooth muscle cell (VSMC) phenotype that contributes to accelerated development of intimal hyperplasia in blood vessels, both de novo and following the arteriovenous anastomosis.
Methods and Results: We examined the effect of culturing human VSMC with human uremic serum on its phenotype. We utilized quantitative real-time PCR to measure the expression of the VSMC-specific contractile marker genes, and found that these genes were reduced 50-80% in VSMC exposed to serum from hemodialysis patients as compared to serum from patients with normal renal function. Chromatin immunoprecipitation assays demonstrated that there were also significant changes in epigenetic markers associated with contractile gene promoters in VSMC cultured in uremic conditions. Moreover, there was a 60% increase in proliferation rate in cells exposed to uremic conditions, with no change in the levels of apoptosis as compared to cells exposed to non-uremic conditions. Interestingly, uremic serum from ESRD patients inhibited PDGF-induced migration of VSMC. We also examined the histopathology of veins from patients with normal kidney function and chronic kidney disease (CKD). Indeed, we found significant de novo venous intimal hyperplasia exists in CKD and ESRD patients prior to any surgical manipulation as compared to veins from patients with normal kidney function.
Conclusion: CKD alters VSMC phenotype in vitro and contributes to intimal hyperplasia formation in vivo resulting in the pathogenesis of vascular access dysfunction in ESRD patients.
Author Disclosures: M. Monroy: None. J. Fang: None. S. Li: None. L. Ferrer: None. I. Lee: None. M.P. Birkenbach: None. E.T. Choi: None.
- © 2014 by American Heart Association, Inc.