William C. Aird, MD
Director, Center for Vascular Biology Research
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, RN-237
Boston, MA 02215
Dr. Aird completed medical school and internal residency training in Toronto, Canada. After completing a fellowship in hematology at the Brigham and Women´s Hospital, Harvard Medical School and a postdoctoral fellowship in the Department of Biology at Massachusetts Institute of Technology, Dr. Aird established an independent research program at the Beth Israel Deaconess Medical Center in 1996. He is currently Director of the Center for Vascular Biology Research and Chief, Division of Molecular and Vascular Medicine at BIDMC, and Professor of Medicine at Harvard Medical School.
Endothelial Cell Phenotypes in Health and Disease
Phenotypic heterogeneity of the endothelium plays a critical role not only in subserving the wide needs of underlying tissues and but also in mediating focal vascular pathology. As much as our appreciation of endothelial cell heterogeneity has evolved over the last two decades, our fundamental understanding of the molecular basis of vascular diversity remains poorly developed.
My lab is focused on understanding the proximate and evolutionary mechanisms underlying endothelial cell heterogeneity. To that end, we have focused on three related areas.
Mechanisms Underlying Vascular Bed-specific Gene Expression
We have developed novel tools for dissecting mechanisms of vascular bed-specific gene regulation, including a plug-in-socket approach for targeting a single copy transgene to a defined locus of the mouse genome by homologous recombination. Our studies have revealed a model of modular gene regulation in which the expression of a single gene within the vascular tree is governed by a constellation of vascular bed-specific signaling pathways that begin in the extracellular milieu and end at distinct regions of the promoter. The ultimate goal of this work is to develop a foundation for selectively targeting subsets of endothelial cells in the intact vasculature.
Spatial and Temporal Regulation of Endothelial Cell Signal Transduction
Using a combination of in vitro and in vivo assays, including sepsis models, we have demonstrated that different activation agonists (e.g., vascular endothelial growth factor, thrombin, tumor necrosis factor, and endotoxin) trigger overlapping yet distinct downstream signaling pathways, and that the net effect of a given agonist depends on the history of signal input (i.e., the set point of the cell). The goal of these studies is to understand how we can selectively alter the extracellular microenvironment and/or intracellular signaling to achieve site-specific modulation of endothelial phenotypes.
Evolutionary Origins of Endothelial Heterogeneity
This pursuit is inspired by our belief that every biological trait requires both proximate and evolutionary explanations, and that the phylogeny of the endothelium holds important clues about its core properties and design constraints (i.e., vulnerability to disease). We have shown that the endothelium in hagfish, the oldest extant vertebrate, is heterogeneous in both structure and function. We are presently using molecular tools to explore the phylogenetic history of several functions of the endothelium, including leukocyte trafficking and hemostasis.
News and Noteworthy Publication
View all publications via PubMed >>
Abid MR, Guo S, Minami T, Spokes KC, Ueki K, Skurk C, Walsh K, Aird WC. Vascular endothelial growth factor activates PI3K-AKT-Forkhead signaling in endothelial cells. Arterioscler Thromb Vasc Biol 2004;24:294-300.
This was the first study to demonstrate a role for forkhead transcription factors in endothelial biology. The study has been followed by several reports (from our lab and others) demonstrating the importance of forkhead signaling in mediating critical functions of the endothelium, e.g. angiogenesis.
Yano K, Liaw PC, Mullington JM, Shih SC, Okada H, Bodyak N, Kang PM, Toltl L, Belikoff B, Buras J, Simms BT, Mizgerd JP, Carmeliet P, Karumanchi SA and
Aird WC. Vascular Endothelial Growth Factor is an Important Determinant of Sepsis Morbidity and Mortality. J Exp Med 2006;203:1447-58. (featured in Nature Reviews Drug Discovery, 2006;5:1).
Here, we showed that circulating levels of VEGF are increased in mice and humans with sepsis and that VEGF signaling is associated with increased morbidity and mortality in mouse models of sepsis. The data were later confirmed by other groups, and have led to new translational efforts to target VEGF in sepsis.
Yano K, Gale D, Massberg S, Cheruvu PK, Monahan-Earley R, Morgan ES, Haig D, von Andrian UH, Dvorak AM, and
Aird WC. Phenotypic heterogeneity is an evolutionarily conserved feature of the endothelium. Blood. 2007;109:613-615.
In this study, we demonstrated that the endothelium of hagfish, the oldest extant vertebrate, displays heterogeneity in structure and function. These data, together with those of a subsequent paper published by our group in the American Journal of Physiology, suggest that phenotypic heterogeneity was present in the ancestral vertebrate and represents a core property of the endothelium.
Okada Y, Yano K, Jin E, Funahashi N, Kitayama M, Doi T, Spokes K, Beeler DL, Shih SC, Okada H, Danilov TA, Maynard E, Minami T, Oettgen P,
Aird WC. A 3-Kb fragment of the human Robo4 promoter directs cell type-specific expression in endothelium. Circ Res. 2007;100:1712-22.
In this report, we identified and characterized a region of the Robo4 promoter that contains information for endothelial cell-specific expression in vitro and in vivo. The data are important because they extend the observation that different promoters direct expression to distinct vascular beds (in this case to the microvessels), and because they provide evidence for the role of a novel Ets binding protein in the endothelium, namely GABP.
Aird WC. Phenotypic heterogeneity of the endothelium. Part I Circ Res. 2007;100:158-173; Part II Circ Res. 2007;100;174-190. This two-part review summarizes the field of endothelial cell heterogeneity, incorporating many of the findings, models and themes generated in our lab over the past several years.