Vyacheslav A. Korshunov, Ph.D.
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Vyacheslav "Slava" A. Korshunov , Ph.D.
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Research
- Flow-induced vascular remodeling is genetically determined and associated with cardiovascular morbidity and mortality
Background
Dr. Korshunov earned his Ph.D. in Pharmacy/Pharmacology from The Pyatigorsk State Academy of Pharmacy (Russia) in 2000, where he was studied several aspects of regulation of cardiovascular function in rodents. In particular, he compared cardiovascular effects of two pharmacological groups of antidepressants and showed an important role of nitric oxide. He was focused on neurogenic mechanisms of arrhythmias after Endothelin-1 in conscious mice. He was also shown that alteration of baroreflex sensitivity to phenylephrine associated with Y-chromosome and mitochondrial DNA in development of spontaneous hypertension in reciprocal crossing of the SHR-SP and WKY rats, while peripheral vascular resistance was not corroborated in this processes.
His post-doctoral training was done in the Center for Cardiovascular Research at the University of Rochester in 2001-2003, in Dr. Bradford Berk’s laboratory. Currently, he is an Assistant Professor in Medicine in the Cardiovascular Research Insitute. Dr. Korshunov’s research interests include the mechanisms underlying genetic effects of the vascular adaptations to flow alterations and its impact on the progression and treatment of cardiovascular diseases.
Research Overview
Every year millions of individuals are diagnosed having coronary disease, and approximately a million myocardial infarctions and 500,000 coronary deaths reported per year in the United States alone. A critical role for low endothelial shear stress and plaque burden (clinically defined as intima-media thickening (IMT)) was found in a number of clinical trials. But mechanism by which vessel remodel remains unclear. We have developed a flow-dependent model of vascular remodeling in a mouse. In fact, this animal model significantly reproduced characteristics of human diseased arteries also called a “Glagov’s phenomenon”.
Both animal experiments and human epidemiological studies suggest a significant genetic factor in vascular remodeling. Our recent observations in low flow-induced vascular remodeling in 5 inbred mouse strains emphasized the role of genetic factors in the ability of blood vessels to obey “Glagov’s phenomenon”. First, according to “Glagov’s phenomenon” there was a significant correlation between increased IMT and increased external elastic lamina (EEL) to maintain lumen diameter constant and therefore flow constant. However, there were also significant strain-dependent differences in the remodeling index (measured as the slope of EEL/IMT). For example, FVB mice increased EEL twice as much as SJL mice for the same increase in IMT. The difference in remodeling index among these mouse strains proves that vascular remodeling has strong genetic influences and suggests that fundamental alterations in sensing changes in blood flow and/or transducing hemodynamic signals contribute to these genetic differences. Since shear stress did not differ among strains (implying normal endothelial function), a primary role for cells in the vessel wall (as opposed to endothelial cells only) is suggested to be essential for vessel remodeling.
To evaluate the role of the two major matrix-degrading systems, plasminogen activators (PAs) and matrix metalloproteinases (MMPs), we compared the expression of u-PA, t-PA, MMP-2 and MMP-9 in ligated carotids of C57 and FVB mice. The PA expression correlated with IMT after flow reduction with large increases in t-PA and u-PA, which was correlated with a greater IMT response in FVB mice. The expression of MMP-2, MMP-9 and TIMP-2 increased with remodeling, but did not exhibit strain-dependent differences. In addition, monocyte/macrophage infiltration and cell proliferation differed between strains, with greater increases in FVB.
In our genetic screen, SJL carotids exposed to low flow were most likely exhibit lumen reduction and fail Glagov’s phenomenon. SJL mice also exhibited the greatest content of inflammatory cells in low flow carotids. By microarray analysis the inflammatory cytokines IL-18 and macrophage migration inhibitory factor (MIF) were shown to be markedly increased in SJL mice compared to C3H mice.
Taken together with current knowledge from clinical trials we can speculate that the early remodeling responses to changes in flow are highly regulated by genetic factors. Identifying these factors may yield new therapeutic strategies to treat vascular diseases.
To appreciate complexity of remodeling process we also used a single gene approach to demonstrate that a receptor tyrosine kinase, Axl (Ark, Ufo, Tyro7) play a significant role in vascular remodeling. In particular, we have found that Axl is an important signaling mediator for oxidative stress in cultured vascular smooth muscle cells and intact vessels. Intimal proliferation and medial growth were significantly decreased in a cuff injury model in Axl knockout mice compared with wild-type mice. Recently we demonstrated an important role for Gas6/Axl pathway in flow-dependent remodeling by regulating not only apoptosis of carotid IMT but also vascular inflammation. Future investigations of the mechanism(s) of Axl in vascular remodeling may yield new therapeutic approaches to diseases such as carotid and coronary IMT.
In addition, the beneficial role of increased flow in carotid arteries was studied in New Zealand genetically hypertensive (GH) rats. Dual inhibition of angiotensin-converting enzyme (ACE) and endopeptidase (omapatrilat) significantly augmented carotid remodeling in response to increased flow in GH rats compared with ACE inhibition alone. This data suggest that vasoactive peptides may improve clinical outcomes in essential hypertension after omapatrilat by promoting remodeling. The mechanism(s) by which vasoactive peptides affect remodeling yet to be determine.
Recent Publications
- Korshunov VA, Mohan AM, Georger M, Berk BC Axl, a receptor tyrosine kinase, mediates flow-induced vascular remodeling. Circulation Research, 2006, V. 98(11), 1446-1452.
- Korshunov VA and Berk BC. Flow-induced vascular remodeling (book chapter). IN: A Handbook of Mouse Models for Cardiovascular Diseases, edited by Quingbo Xu, 2006, 103-112.
- Korshunov VA, Nikonenko TA, Tkachuk VA, Brooks A, Berk BC. Interleukin-18 and macrophage migration inhibitory factor are associated with increased intima-media thickening. Arteriosclerosis, Thrombosis, and Vascular Biology, 2006, V. 26(2), 295-300.
- Korshunov VA, Solomatina MA, Plekhanova OS, Parfyonova YeV, Tkachuk VA, Berk BC Plasminogen activator expression correlates with genetic differences in vascular remodeling. Journal of Vascular Research, 2004, V. 41, #6, 481-490.
- Korshunov VA, Berk BC. Strain-dependent vascular remodeling. The “Glagov phenomenon” is genetically determined. Circulation, 2004, V.110, 220-226.
- Konishi A, Aizawa T, Mohan A, Korshunov VA, Berk BC. Hydrogen peroxide activates the Gas6-Axl pathway in vascular smooth muscle cells. Journal of Biological Chemistry, 2004, V.279, #27, 28766-28770.
- Korshunov VA, Massett MP, Carey RM, Berk BC. Role of angiotensin converting-enzyme and neutral endopeptidase in flow-dependent remodeling. Journal of Vascular Research, 2004, V. 41, #2, 148-156.
- Korshunov VA, Berk BC. Flow-induced vascular remodeling in the mouse: a model for carotid intima-media thickening. Arteriosclerosis, Thrombosis, and Vascular Biology, 2003, V.23, #12, 2185-2191.
- Korshunov VA, Murashev AN, Ivashev MN, Dugin SF, Medvedev OS. Hemodynamic effects of tetrindol in alert normotensive mice and rats after blockade of nitric oxide synthesis. Bull. Exp. Biol. Med., 2000, V.130, #8, 193-195.
- Monastyrskaia EA, Murashev AN, Khokhlova ON, Saprunova VB, Korshunov VA, Koshelev VB. Genetic aspects of arterial hypertension: the role of Y chromosome and mitochondrial DNA (Russian). Russ. J. Physiol. (formely I.M. Sechenov Physiol. J.), 2000, V.86, #6, 671-680