Vascular Biology Interest Group

Co-chairs: Dr. Ramani Ramchandran and Dr. Ravi Misra

Investigators/members


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.
	Kelly Duffy, PhD The objective of my research is to identify and characterize the roles of novel candidate genes and proteins involved in the development of the lymphatic vasculature in both normal and pathologic conditions, primarily lymphatic malformations, using a combination of genetic, proteomic, and developmental biology approaches. While the blood vascular system has been well studied, progress in our understanding of the lymphatic vascular system has been hindered by a lack of available model systems. Our translational and multidisciplinary work has allowed for the development of novel approaches to isolating and culturing lymphatic endothelial cells (LECs) from patients with lymphatic malformations in collaboration with pediatric interventional radiologists at MCW, as well as the assessment of candidate protein expression in the mouse embryo at various time points during the development of the lymphatic vasculature. We believe the use of LECs derived from lymphatic malformations will allow for the identification of dysfunctional genes/proteins that will not only provide new information regarding their pathogenesis, but will also provide critical data regarding normal lymphatic development and behavior.
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.
	Mary Holtz, PhD As a member of Dr. Ravi Misra's research laboratory, our work is designed to investigate cardiovascular function and development. More specifically, it focuses on the transcriptional regulation of genes involved with vascular development. Our research provides insight into normal cardiac function in the adult as well as clues to genetic causes of congenital malformations of the cardiovascular system. Additionally, the information gained from our studies may be useful in developing treatments aimed at restoring cardiovascular function after injury such as a heart attack, or as a result of chronic disease such as hypertrophic cardiomyopathy.
Jian Huang, MD Angiogenesis is a critical aspect of development and progression in tumor. As a trained research pathologist, Dr. Huang is actively involved in the Developmental Vascular Biology Program to provide pathology related services/consults to all research projects. Dr. Huang is a faculty in the department of pathology at MCW. He has over 20 years experience in cancer research. Dr. Huang had been participating in many large breast cancer related research projects during the last six years. These research projects included Breast SPORE, PPG, Susan G. Komen and R01 grants. Currently, Dr. Huang oversees the process of tissue procurement and tissue quality control for the MCW tissue bank and also provides pathology related services/consults to all MCW faculty for their research projects.
	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.
	Kimberly Pechman, PhD A primary focus of my research is the application of MRI methods to assess brain tumor angiogenesis and invasion in preclinical models. One of the hallmarks of glioblastoma brain tumors is the high level of new vessel growth or angiogenesis required for progression from low-grade to high-grade tumors. Angiogenesis is influenced by a balance between proangiogenic and antiangiogenic factors. Despite the early promising results with anti-angiogenic therapies to prolong the time to progression, the optimal dose and drug combinations have not yet been defined. By using MRI methods developed in our laboratory capable of measuring the amount of blood volume in the brain and tumor (cerebral blood volume [CBV]), we can provide information about tumor biology that is not currently available with standard MRI. In addition, we have used CBV to characterize, optimize, and track the response of brain tumors to combination anti-angiogenic therapy and chemotherapies in preclinical models. Our results demonstrate rCBV can provide a more complete assessment of the tumor in determining the optimal temporal therapeutic paradigms in preclinical studies and may likewise assist in more effective design treatment paradigms for malignant gliomas in patients. The permeability MRI studies performed can also provide more information about the tumor biology and track tumor progression and responses to therapy.
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.
	Bin Ren, MD PhD The Vascular Pathobiology program investigates molecular mechanism of angiogenesis (the formation of new blood vessels) and arteriogenesis (the growth of new functional arteries). Understanding the mechanism would be of great advantage to our understanding of the pathobiology of ischemic cardiovascular disease and malignant tumors. The long-term goal of our research is to determine the molecular signaling of angiogenesis and arteriogenesis, and to develop molecular strategies for stimulating or inhibiting the growth of new vasculature. We study how protein kinase D-1 signaling initiates a transcriptional program to regulate angiogenic program and the arteriogenesis that occurs during development or in the adult circulation. To accomplish this study, we will utilize a unique endothelial cell model, and a conditional endothelium specific PKD-1 transgenic mouse model. The unique PKD-1 transgenic mouse model can spatially and temporally control constitutively active PKD-1 gene expression in the endothelium lining the vessel walls. These tools will aid in the discovery of signaling molecules that are critical to the arteriogenesis. Thereby, we can target the crucial molecular signaling pathway in the arteriogenesis as a therapeutic strategy for the ischemic heart and vascular diseases and the malignant tumors.

Dawn Siegel, MD Dr. Siegel is the director of the PHACE Syndrome International Clinical Registry and DNA repository and the Vascular Genetics Translational Research and Gene Discovery Program at Children's Hospital of Wisconsin. In these programs, we use copy number variation analysis and next-generation sequencing to discover the genetic basis of vascular anomaly syndromes. In addition, we are performing natural history studies for these cohorts.
	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.
Ru-Jeng Teng, PhD Our group investigates pulmonary vascular biology during the newborn period. Using in utero ligation of ductus arteriosus of fetal sheep as the animal model for persistent pulmonary hypertension of the newborn (PPHN) we explore the mechanisms that lead to impaired blood vessel formation in the lungs and impaired pulmonary vasodilation in PPHN. Increased reactive oxygen species formation is shown by us to be a major player for the impairments. Understanding the mechanisms for PPHN has lead to several potential terapeutic modalities. We also extend our study into the roles of mitochondria, prostaglandins, antioxidant systems and reactive nitrogen species in PPHN and hyperoxic lung injury in neonates. The studies are translational and may help preventing neonates from chronic lung disease.
	George Wilkinson, PhD Endothelial cells contribute to lung alveolar formation. 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. ECSCR is a novel endothelial-specific gene with roles in vasculogenesis and proliferation. We are also studying a novel endothelial gene product, Endothelial cell-specific chemotactic receptor (ECSCR, formerly known as ECSM2). The ECSCR open reading frame 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.
Hao Xu, PhD My lab examines the mechanisms by which oxidatively modified extracellular matrix, specifically 4-hydroxynonenal modified fibronectin induces atherosclerosis. Although high levels of low-density lipoprotein (LDL) are well recognized as a major risk factor for heart disease, recent studies have shown that roughly 75% of hospitalized coronary artery disease patients had LDL-cholesterol levels <130 mg/dL, indicating that factors beyond LDL may play a role in the mechanisms for inducing endothelial dysfunction and atherosclerosis. Findings from our studies will reveal new insight into the mechanisms driving atherosclerosis beyond those induced by LDL-cholesterol that may be useful for developing new drugs and identifying different targets to prevent atherosclerosis.
	Chen Yiliang, PhD CD36 is expressed in microvascular endothelial cells and functions as a negative regulator of angiogenesis. Therefore, the signaling through CD36 plays essential roles in tumor growth, inflammation, wound healing and other processes requiring neovascularization. CD36 expression can be regulated at the transcriptional level, which may represent a key mechanism for angiogenic switch. Via collaborating with my colleague, Dr. Bin Ren, we study a PKD-1-mediated signaling pathway that regulates the CD36 expression and signaling in endothelial cells. We are using various transgenic and knock out mice models to characterize the function of this signaling pathway in vivo.