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