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Vascular Biology Interest GroupCo-chairs: Dr. Ramani Ramchandran and Dr. Ravi MisraMCW Faculty Collaboration Database Investigators/members:
Andrew Chan, PhD |
Members of the Ras subfamily of small GTP-binding proteins play critical roles in a wide spectrum of biological processes. With more than twelve evolutionary conserved members, individuals' G-proteins are predicted to propagate unique upstream signals in a tissue specific manner. One such member, R-Ras, is expressed in endothelial and vascular smooth muscle cells. In stark contrast to the prototypic Ras oncogenes, R-Ras regulates cell adhesion in response to signals initiated at the cell-cell junction by members of the semaphorin and plexin family of proteins. In addition, active R-Ras is localized to specific subcellular compartments including endosomes and the endoplasmic reticulum, where it promotes calcium-dependent exocytosis. Our laboratory is currently focusing on understanding the signaling mechanisms R-Ras utilizes in regulating angiogenesis using both primary cell culture systems and in vivo models.  |
|  Kelly Duffy and Beth Drolet, MD | Our research focuses primarily on vascular malformations and various overgrowth syndromes that are associated with them. We currently are conducting gene and protein expression pathway profiling studies on patients with various vascular malformations in an effort to better characterize this diverse patient population on the molecular level. In addition, we work on studies assessing the genetic analysis of hemangiomas, a type of vascular tumor, using high-density SNP arrays. John Imig, PhD |
The long-term research goal of my laboratory is the elucidation of mechanisms by which eicosanoid metabolites influence cardiovascular function. Over the past decade, considerable interest has focused on the eicosanoid pathway. Substantial evidence has accumulated, demonstrating that eicosanoid metabolites are involved in the regulation of vascular function and contribute to the integration of cardiovascular function. Altered production of eicosanoid metabolites contributes to the pathology associated with many diseases including hypertension, diabetes, cardiometabolic syndrome and stroke. Although the importance of the eicosanoid pathway now is well-recognized, many aspects concerning cell-signaling and pathophysiological role of eicosanoid metabolites remain unresolved. Ongoing investigations of eicosanoid metabolites in the laboratory have led to the discovery of novel therapeutic targets for cardiovascular diseases.
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 Girija Ganesh Konduri, MD | Our lab is interested in the mechanisms of vascular dysfunction in persistent pulmonary hypertension of newborn. PPHN affects newborn infants during their transition to postnatal life and leads to hypoxemia and acidosis. We investigate the altered eNOS function in pulmonary arteries in this disease using a fetal lamb model with PPHN induced by prenatal ductal ligation. We observed an increase in oxidative stress in this model resulting from uncoupled eNOS activity. We also observed an increase in mitochondrial oxidative stress in this model and both sources appear to impair in vitro angiogenesis and vasodilator responses. We currently are investigating the time course of vascular dysfunction, mechanisms of eNOS uncoupling and strategies to improve the vascular function in PPHN. |
| Meetha Medhora, PhD |
Our laboratory is studying the effect of ionizing radiation on the vasculature of the lungs. We also are interested in the vaso-reactive and anti-apoptotic actions of EETs and 20-HETE (products of the essential fatty acid, arachidonic acid) on blood vessels. Effects of ionizing radiation on the vasculature of the lungs. As part of The Medical College of Wisconsin Center for Countermeasures Against Radiation, we are identifying agents to mitigate radiological injury to the lungs. Using a rat model, we have observed a single non-lethal dose of 10-15 Gy to the thorax to result in vascular injury after six to eight weeks. Specifically in collaboration with the laboratory of Dr. Robert Molthen, an engineer at the Zablocki VA Medical Center, we measured a reduction in density, reactivity, distensibility and endothelial function accompanied by an increase in resistance in the pulmonary vasculature. All of the injuries except for vascular distensibility recover by one year. Currently we are testing a number of pharmaceutical reagents in an effort to identify mitigators and treatment for the radiation pneumonitis we observe. Vasoreactive and antiapoptotic actions of EETs and 20-HETE (products of the essential fatty acid, arachidonic acid). The endogenous fatty acids EETs and 20-HETE have potent vasoreactive and other properties. In collaboration with the laboratory of Dr. Elizabeth Jacobs, we have demonstrated that EETs protect pulmonary arteries ex vivo using vessels from three species; human, mouse and rat. 20-HETE also protects rat pulmonary and cerebral arteries from hypoxia and reoxgygenation injury ex vivo. We currently are studying the intracellular mechanisms for protection by these fatty acids. | |
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 Robert Miao, PhD | Our laboratory's current research effort focuses on two areas. The first is to utilize molecular biology and cell biology approaches to elucidate the role of Nogo-B receptor (NgBR) in regulating stem cell differentiation to vascular cell lineages, primitive blood vessel formation during embryo development and postnatal blood vessel formation during tumor growth and other vascular diseases. The second focus is on are establishing in vitro and in vivo models to dissect the molecular mechanisms in regulating the interaction of endothelial cells with microenvironment niche during vasculogenesis and angiogenesis, and developing therapeutic approaches to modulate Nogo-B/NgBR functions in vivo. |
| Ravi Misra, PhD |
We are interested in understanding transcriptional regulatory mechanisms that underlie the earliest stages of coronary vascular development. We are looking at the role of the SRF transcription factor in endothelial differentiation of cells derived from the proepicardium, and the role of SRF in function of differentiated endothelial cells. In addition, the ability of proepicardial cells to effect vascular repair of myocardium also is being investigated. | |
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| Michael Mitchell, MD, and Aoy Mitchell, PhD Development and utilization of high-throughput methodologies for identifying inherited risk factors, genetic and molecular etiology of congenital heart disease, and mutation detection technologies. |
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 Paula North, MD, PhD | Vasculogenesis and hemangioma. |
| Ramani Ramchandran, PhD |
The Developmental Vascular Biology program investigates the basic mechanisms of blood vessel formation in vertebrates and the contribution of the vasculature to disease states. We study how a specified endothelial precursor cell (angioblast) eventually differentiates into artery or vein. The basic mechanisms of this process often are deregulated in disease. Understanding the basic mechanisms of vessel formation will generate new treatments for conditions affected by deregulated vessel growth. In particular, vascular conditions associated with children such as hemangiomas and solid tumors will benefit because ongoing studies in this program utilize developing zebrafish and mouse embryos. Zebrafish studies specifically are primarily embryonic in nature and directly contribute to child development. Tools for performing drug screens using zebrafish embryos are being developed, which will identify targets and potential drug leads for treating vascular conditions. |  |
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 Tara Sander, PhD | Dr. Sander's research interests include studying molecular mechanisms that regulate vascular endothelial cell function. Her goal is to understand how disruptions in these mechanisms contribute to the pathogenesis of congenital and acquired vascular diseases including valvular heart disease, acute lung injury, vascular anomalies and cancer. She also participates in translational research activities, bridging the areas of vascular biology and clinical molecular diagnostics. Her goal is to work with investigators to identify genetic variations that cause congenital disorders and translate these discoveries to the clinic for the development of diagnostic tests for the pediatric population. |
| Rashmi Sood, PhD |
We study the vascular bed of the placenta and the mechanism of pregnancy-related cardiovascular disorders. The human placenta forms a highly specialized and unusual vascular bed. Local abnormalities in this vascular bed not only affect fetal nutrition and development, but through the continuum of maternal circulation also affect maternal physiology and health. We develop and utilize rodent models of pregnancy disorder associated with vascular disease, such as thrombophilia, to arrive at a mechanistic understanding of these disorders. | |
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Dorothee Weihrauch, DVM, PhD | Coronary collateral growth and impaired angiogenesis in diabetes include some of Dr. Weihrauch's current research interests. The tools used in her laboratory are protein analysis, proliferation assays, migration assays on cultured cells as well as histology and immunohistochemistry. Dr. Weihrauch's laboratory investigates growth factors, growth inhibitors and the role of lipoproteins in this process. Additional research interests involve elucidating the signal transduction pathway of anesthetic-preconditioning, delayed preconditioning and post-conditioning in euglycemia and hyperglycemia. |
| George Wilkinson, PhD |
Blood vessels become adapted during development according to specific needs of the organ they supply. One organ system that is highly vascularized is the lungs. In the lungs, the vasculature becomes highly specialized to provide efficient gas-exchange by participating with alveoli. Development of lung alveoli requires complex interactions among blood vessels, other specialized cells and the extracellular matrix. Defects in any one of these elements will adversely affect alveolar development. Human lung pathologies including emphysema and infant bronchopulmonary dysplasia are associated with defective alveolar structure and concomitant vascular pathologies. Our lab is studying a hypomorphic allele of the vascular gene ephrinB2. Lungs of mice homozygous for this allele fail to develop alveoli, suggesting requirement for vascular signaling at an early stage of alveolar formation. We would like to know how ephrinB2 and its receptors contribute to this process. We also investigate novel gene candidates that play roles in vasculogenesis. One such candidate is ECSCR, a novel endothelial-specific gene with roles in vasculogenesis and proliferation. Endothelial cell-specific chemotactic receptor (ECSCR, formerly known as ECSM2) has an open reading frame that encodes a transmembrane protein of 205 amino acids with no homology to any other known protein. In collaboration with Dr. Ramchandran, we are studying ECSCR using a combination of zebrafish methods, cell culture, and mouse genetics. |  |
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Magdalena Chrzanowska-Wodnicka, PhD | Rap1 is an evolutionary conserved and ubiquitously expressed small GTPase which becomes activated downstream from multiple surface receptors. Well-studied in vitro, Rap1 has been shown to regulate several basic cellular functions: adhesion, migration, polarity, differentiation and growth. However, the role of Rap1 in mammalian systems in vivo still is not very well understood. Using murine Rap1b-deficiency model, we are investigating the function of Rap1 in the cardiovascular system in vivo, ex vivo, and, to understand the underlying mechanisms - in vitro using primary vascular cells. Our recent studies have revealed a novel role of Rap1b in vivo; regulation of angiogenesis. In an in vivo neonatal retinal model and a Matrigel plug model, we demonstrated that Rap1b-deficiency leads to a defect in angiogenesis. Through ex vivo and in vitro studies, we localized the defect to endothelial cells and show that endothelial proliferation and migration are affected by Rap1b-deficiency. At the molecular level, the underlying mechanism involves defective signaling from VEGF Receptor 2. Current research is focused on elucidating molecular mechanisms through which Rap1 regulates VEGFR2 signaling in angiogenic responses of endothelial cells.
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Presentations
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