News and Publications

Chairman's Overview

David J. Loskutoff, Ph.D.

Vascular biology is the study of blood vessels, and of the lipids, proteins, cells, and "factors" that circulate within the vessels. The vascular system is a unique and rather important subject for investigation. It is the largest and perhaps the most complex structure in the body, and vascular disease is the most common cause of death and disability in Western societies. Moreover, although vascular cells are an integral part of all tissues, they are not the same in all tissues, and they appear to undergo tissue-specific functional differentiation. These considerations emphasize the unique challenges facing investigators trying to understand vascular structure and function and attempting to define the rules that govern the complex interactions between the vessel wall and circulating blood components.

Despite this complexity, members of the Department of Vascular Biology have been remarkably successful in their studies, and they continue to make seminal contributions to our understanding of vascular cell biology. Perhaps the best illustration of this was the selection of 9 members from the department--Drs. Cheresh, Edgington, Ginsberg, Loskutoff, Madison, Ruf, Ruggeri, Schwartz, and Shattil--to provide keynote lectures at a recent Gordon Conference on vascular cell biology and hemostasis. The department was also selected to host the VIth International Workshop on the Molecular and Cellular Biology of Plasminogen Activation last year in San Diego. This selection was significant, because this workshop is considered by many to be one of the most important meetings in the field. In this report, I briefly highlight some of the specific accomplishments of our investigators. Although no overview can provide the interesting detail of the individual studies, I hope this brief summary will stimulate you to read the more complete reports that follow.

One of the major research themes of the department continues to be vascular cell-mediated proteolysis and its regulation by inhibitors, cofactors, receptors, and the extracellular matrix. For example, in my laboratory, we are using various mouse models (e.g., sepsis, obesity, glomerulonephritis) to define the contribution of plasminogen activator inhibitor-1 to the pathogenesis of cardiovascular disease. The molecular mechanisms by which this protease inhibitor regulates the ability of vascular cells to adhere to and migrate on the extracellular matrix protein vitronectin are also being studied. Dr. F. Samad is investigating the mechanisms by which insulin and TNF- alter glucose metabolism and regulate expression of the gene for plasminogen activator inhibitor-1 in insulin-resistant adipocytes and mice.

Dr. R. Schleef has discovered a new serine protease inhibitor and is trying to identify the protease it regulates and to define the role of the inhibitor in cell growth, cell death, and differentiation. Dr. L. Miles is using novel approaches to purify, clone, and characterize receptors that localize proteases to the cell surface. She is also studying regulatory lipoproteins and components of the extracellular matrix and is trying to define the pathway by which the synthesis and secretion of the protease tissue plasminogen activator are controlled in the brain. Tissue plasminogen activator is a primary activator of plasminogen in vivo and has been implicated in stroke. In this regard, Dr. E. Madison is studying structure-function relationships in the proteases tissue plasminogen activator and urokinase. His studies are providing important insights into the rules that govern protease zymogenicity and the substrate and inhibitor specificities of the proteases.

Besides studying extracellular proteolysis and its role in vascular function, members of the department are also investigating structure-function relationships in vascular integrins and are trying to delineate the complex signaling cascades used by integrins to regulate vascular cell behavior. For example, Dr. Y. Takada is doing mutagenesis studies on integrin and ß subunits in an attempt to systematically define the regions of the subunits required for specific interactions with fibrinogen, von Willebrand factor, vitronectin, vascular cell adhesion molecule, and fibronectin. Dr. T. O'Toole is studying the cytoplasmic domain of integrins in an attempt to delineate regions of the integrin molecules that bind to cytoplasmic proteins and govern signaling. Dr. M. Schwartz is investigating how integrins actually transduce the signals that regulate cell growth, migration, and survival. Researchers in his laboratory have identified specific downstream mediators of integrin signaling. Dr. M. Ginsberg and his collaborators are studying fundamental mechanisms by which integrins become activated. These investigators have developed a novel complementation approach and have used it to identify CD98 as a new player in integrin signaling pathways. Finally, Dr. S. Shattil is studying mechanisms of signal transduction in platelets.

In summary, the past year has been extremely successful for the department in terms of scientific accomplishments, the maturation of ongoing projects, and the development of new research programs. Members of the department have been visible contributors to a variety of important national and international meetings dealing with fundamental and clinical aspects of vascular biology. All of these achievements have occurred with significantly increased funding from the National Institutes of Health. The department continues to organize the Vascular Biology Lecture Series, the Vascular Biology Retreat, and the Vascular Biology Holiday Party.

The department also provides a focus for investigators who share common interests in proteases, integrins, cell adhesion molecules, and cardiovascular disease but have primary appointments in other departments. Many of these scientists have joint appointments in The Department of Vascular Biology. Their studies on the biochemistry and cell biology of thrombosis, hemostasis, fibrinolysis, stroke, atherosclerosis, and angiogenesis nicely complement our own and create a powerful vascular biology program at TSRI. A vascular biology working group was recently organized as a way to further promote the interests and facilitate the interactions between members of the vascular biology community at TSRI.

Finally, I am sad to report that Ed Madison has decided to leave TSRI to pursue studies at a local biotechnology company. Ed is an excellent scientist and a good colleague, and we wish him success. We are interviewing potential new faculty members to replace him. When our new member is established, we will be in a strong position to continue to build on our previous record of accomplishments.