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Department of Pharmacology

Department of Pharmacology
 

Mary Weiser-Evans, PhD

Associate Professor


Contact Information:

University of Colorado Denver
Department of Renal Medicine and Hypertension
Mail Stop 8303, RC2
12700 East 19th Ave
Aurora CO 80045

Phone: (303) 724-4846
Fax: (303) 724-4868
E-mai: mary.weiser@ucdenver.edu
curriculum vitae

Affiliated Programs

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​Regulation of vascular smooth muscle cell function and neointima formation.

Restenosis and excessive vascular smooth muscle cell (SMC) proliferation is one of the major limitations of percutaneous angioplasty procedures, vascular grafts, and is commonly observed with vascular access dysfunction in dialysis patients. SMC accumulation in the arterial intima is a key event in the pathogenesis of many vascular diseases, including post-angioplasty/in-stent restenosis, atherosclerosis, and pulmonary hypertension, and is characterized by the dedifferentiation, migration, and proliferation of medial-derived SMC to form the neointima. An injury-induced inflammatory response, which is characterized by bone marrow-derived and/or circulating inflammatory and progenitor cell recruitment to the injured vessel, also contributes to neointimal lesion formation. Several cytokines and chemokines, including MCP-1/JE, SDF-1a, IL-6, and CXCL1/KC, are rapidly induced in vascular wall cells following injury and participate in the remodeling process through the recruitment of inflammatory and vascular progenitor cells. Some of these factors have also been shown to directly affect the biological function and phenotype of the SMC itself placing the SMC as both a mediator and an effector of the injury response. However, the underlying molecular programs activated in SMC in response to injury are not clearly defined. As cell signaling alterations are fundamental in the pathogenesis of vascular proliferative disorders, the studies in our lab are focused on the hypothesis that SMC are central mediators of the injury response with perturbations in SMC signaling resulting in the production of soluble factors that regulate significant SMC hyperplasia and progenitor/inflammatory cell recruitment through autocrine/paracrine mechanisms.
 
Under physiological conditions, the mature blood vessel is a highly quiescent tissue suggesting that pathological vascular remodeling requires the inactivation of active growth inhibitory pathways prior to rendering SMC permissive to growth stimulation. Although mechanisms of endogenous SMC growth inhibition are poorly understood and understudied, our previous work strongly indicates that the phosphatase, PTEN, a negative regulator of PI3-kinase/Akt/mTOR signaling, is a potent, endogenously-produced inhibitor of SMC proliferation and that SMC-specific PTEN inactivation is an early and critical trigger driving vascular lesion formation. To explore the direct role of PTEN in mediating SMC function, using Cre-Lox technology, we generated inducible, SMMHC-CreERT2-mediated SMC-specific PTEN mutant mice (PTEN iKO). Compared to controls, PTEN iKO mice exhibit significant reductions of total PTEN in major vessels with accompanying increased phosphoAkt levels and enhanced neointima formation following carotid arterial injury. PTEN-deficient SMC in vitro exhibit an autocrine growth phenotype under basal conditions and express a cytokine/chemokine profile similar to what is observed in SMC following experimental injury. Preliminary data show that PTEN depletion activates the transcription factors, NFkB and HIF-1a; inhibition of NFkB or HIF-1a blocks the upregulation of specific chemokines mediated by PTEN depletion. On the other hand, published studies demonstrated that activators of the nuclear receptor PPARg attenuate injury-induced vascular remodeling and in other physiological systems, PPARg has been shown to upregulate PTEN expression and/or activity. Our data show that PPARg activation in SMC upregulates PTEN. Therefore we are also examining the ability of PPARg activation to inhibit SMC proliferation and regulate anti-inflammatory responses through the upregulation of SMC PTEN.
 
Overall we are investigating the role of alterations in SMC PTEN signaling as a key initiating determinant driving pathological vascular remodeling through the production of a family of chemoattractants each having distinct physiological effects involved in driving SMC autocrine growth and the recruitment of inflammatory/progenitor cells. We are focused on identifying the molecular mechanisms that regulate PTEN expression/activity in the setting of vascular disease. Our studies have identified multiple factors that downregulate PTEN, including multiple pro-proliferative growth factors and cytokines involved in promoting restenosis and atherosclerosis as well as distinct microRNAs that specifically target PTEN for degradation. In addition, new studies in the lab are focusing on identifying PTEN-regulated microRNAs in order to define a SMC microRNA signature profile affected by alterations in PTEN activity in vascular disease. We hope to identify specific roles for distinct microRNAs that are either up- or downregulated by PTEN signaling. In vivo and in vitro studies will then be designed to analyze their ability to control diverse aspects of vascular disease. Finally, we are examining the ability of PPARg agonists to restore SMC PTEN signaling in order to reverse the cascade of events brought on by vascular injury.
 
Our lab uses in vitro cell culture and co-culture approaches to study the molecular aspects of SMC function and to define interactions of SMC with other cell types known to influence vascular disease, (eg. circulating inflammatory and progenitor cells).  All cell culture studies are complimented with in vivo animal approaches. We have generated novel in vivo mouse models to lineage trace the contribution of vascular smooth muscle compared to bone marrow-derived inflammatory and progenitor cells in response to experimental injury and to examine the specific roles of SMC-derived PTEN, HIF-1a, NFkB, and PPARg in the regulation of pathological vascular remodeling in mouse models of restenosis and pulmonary hypertension. As complications of heart disease are the leading cause of death in Western societies, defining the underlying molecular mechanisms regulating vascular lesion formation is an essential clinical problem.
 
In addition to the vascular biology-related studies, I have been involved in projects related to lung cancer progression and metastasis. In collaboration with Dr. Raphael Nemenoff, we developed a novel lung cancer metastasis model that allows us to examine the role of the lung tumor microenvironment on lung cancer progression and to define specific signaling pathways activated in both cancer cells and the tumor microenvironment that regulate cancer progression. In vitro co-culture systems are used to examine the functional interactions between lung cancer cells and inflammatory cells. We are currently using these systems to examine the role of PPARg and PPARg agonists, specifically pioglitazone, on lung cancer progression and metastasis.
 
Current Research Projects 
The vascular biology studies in our lab are currently funded by an NIH RO1 grant (Weiser-Evans, PI) to study PTEN signaling in restenosis and by an NIH PPG Project (Weiser-Evans and Nemenoff, PIs) to study PTEN signaling in pulmonary hypertension.  Most aspects of the outlined research (from above) are available for a sub-project for interested Pharmacology graduate students. Specific projects will be carefully developed with input from both the Student and Dr. Weiser-Evans.

 

Current Lab Members

 Results From Personnel : Selected site and subsites
First NameLast NameMiddle InitialDegreePosition
HenrickHorita PhDPostdoctoral Fellow