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Evgenia Gerasimovskaya, PhD


Associate Professor

Pediatric Critical Care Medicine
Cardiovascular and Pulmonary Research Laboratory

Contact Information:

University of Colorado Denver​
Pediatric Critical Care Medicine, Box B131
12700 E. 19th Avenue
Research 2, Room 6119
Aurora,CO  80045
Tel: (303) 724-5614-office; (303) 724-5642-lab;
Fax:(303) 724-5631

E-mail: evgenia.gerasimovskaya@ucdenver.edu

Education and training 

·            1982-1987    Lomonosov Moscow State University                   MS

·            1987-1994    Cardiovascular Research Center (Moscow)         PhD

·            1998-1999    Yale University SOM                                             Postdoctoral Fellowship

·            1999-2001    University of Colorado Health Sciences Center    Postdoctoral Fellowship

 

Professional Experience

·         1990-1992        Research Scientist, Cardiovascular Research Center (Moscow)

·         1997                 Research Scholar, University of Pennsylvania

·         1992-1998        Senior Research Scientist, Cardiovascular Research Center (Moscow)

·         2001-2003        Research Associate, University of Colorado Hlth Sci Ctr

·         2004                 Instructor, University of Colorado Hlth Sci C

·         2005-2007        Research Assistant Professor, University of Colorado Hlth Sci Ctr

·         2007-2013        Assistant Professor, University of Colorado Denver

·         2014-present    Associate Professor, University of Colorado Denver

 

Research summary:

My research focuses on the role of the purinergic signaling system in regulation of vasa vasorum angiogenesis and barrier function. Our studies include several directions:


Purinergic regulation of pulmonary artery vasa vasorum angiogenesis in the pathogenesis of pulmonary hypertension

Pathological vascular remodeling is a key component and a frequently life-threatening consequence of vascular diseases in both the systemic and pulmonary circulation. Chronic hypoxia is a significant contributing factor to the development of pulmonary hypertension (PH) and is a potent stimulus for new vessel growth. The vasa vasorum (VV) is a microcirculatory network that provides oxygen and nutrients to the adventitia and media of large blood vessels. We demonstrated that a marked expansion of the VV occurs in the pulmonary artery (PA) adventitia of hypertensive calves, implicating involvement of VV in PH pathogenesis. However, the fundamental cellular and molecular mechanisms contributing to the VV expansion remain largely unexplored.

Extracellular purines  (ATP, ADP and adenosine) are emerging as important signaling regulators of the vascular, immune, and hematopoietic systems. Vascular and blood cells release ATP in response to a variety of pathological conditions, including hypoxia. Using cultured vasa vasorum endothelial cells (VVEC) isolated from the PA of chronically hypoxic hypertensive calves, as a physiologically relevant model system, we demonstrated that VVEC are a potent source of extracellular ATP, which acts as an autocrine/paracrine factor augmenting hypoxia-induced VVEC angiogenesis. We also found that exaggerated nucleotide-mediated angiogenic responses in VVEC (which have not been observed in EC of large blood vessels) involve activation of P2Y1 and P2Y13 purinergic receptors, PI3K/Akt/mTOR and ERK1/2 signaling pathways, as well as the elevation of cytoplasmic, nucleoplasmic, and mitochondrial Ca2+. Ongoing efforts in our lab are aimed at identifying a subset of transcription factors that mediate purinergic receptor-dependent activation of angiogenic responses in VVEC. We also characterize phenotypes and angiogenic properties of highly proliferative progenitor cell sub-populations of VVEC to examine whether P2Y13 and/or P2Y1 purinergic receptors could be potential markers for progenitor cell population and could serve as a novel, previously unidentified pharmacologic targets in regulating vasa vasorum neovascularization.

 

Role of extracellular adenosine in regulating VVEC barrier function

Maintenance of vascular permeability is fundamental to normal blood vessel function and tissue homeostasis. Previously demonstrated that angiogenic expansion of VV network was accompanied by accumulation of circulating progenitor and inflammatory cells in the PA adventitia, which is an event that precedes structural vascular remodeling in pulmonary circulation. Using transendothelial electrical resistance (TER) assay, we showed that adenosine acting via A1 receptors (A1R) prevents hypoxia-induced increase in VVEC permeability, and that A1R expression is downregulated chronic hypoxia. We also found that Gαi/PI3K/Akt and actin cytoskeleton remodeling is downstream of A1R activation, suggesting a non-canonical (possibly cAMP –independent) pathway of VVEC barrier regulation. We are currently examining intracellular signaling pathways and cytoskeleton changes underlying the A1R-mediated barrier protective effect in VVEC. In addition, utilizing Sprague Dawley model of hypoxia-induced PH and ex vivo two photon confocal microscopy, we use fluorescent-labeled lectins and dextrans to visualize the effect of hypoxia on VV angiogenesis and permeability. Our studies will also validate a barrier protective effect of adenosine and A1R agonists to determine whether A1R can be recognized as a vascular bed-specific and novel therapeutic target to regulate vasa vasorum barrier function and pathologic vascular remodeling in chronic hypoxia.

 

Role of cellular energy pathways in VVEC angiogenesis

​Despite the evidence that angiogenesis requires replication of energetically competent cells, it remains under investigated how cellular metabolism affects the angiogenic state of the cells and if cellular metabolism is regulated by extracellular signals. To fill this gap, our studies focus on a mechanistic link between purinergic receptor-mediated angiogenic signaling, cellular energy pathways and VVEC phenotype. By using pharmacological inhibitors of glycolysis and mitochondrial respiration, we investigate the potential role of glycolysis and oxidative phosphorylation (OXPHOS) to ATP-stimulated VVEC angiogenesis. Our data demonstrated that activation of purinergic receptors increased both OXPHOS and mitochondrial Ca2+ in VVEC. In order to obtain a detailed characterization of the effects of extracellular nucleotides and hypoxia on VVEC bioenergetics, the rate of oxidative phosphorylation (oxygen consumption rate, OCR) and glycolysis (extracellular acidification rate, ECAR) will be simultaneously measured over time in intact cells using XF24 Extracellular Flux Analyzer (Seahorse Bioscience). Our current focus is also to define metabolic phenotypes of angiogenically activated VVEC and to determine whether changes in cellular metabolism affect VVEC expression of endothelial and progenitor markers, as well as purinergic receptor subtypes.

 

Key words: vasa vasorum, angiogenesis, hypoxia, pulmonary hypertension, vascular remodeling, purinergic receptors, extracellular purines, ATP, cell signaling

 

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