Research: Vascular Inflammation



Vascular inflammation is associated with several diseases. The most common disease in the United States is coronary heart disease. The underlying disease process resulting in coronary heart disease is atherosclerosis. This process is initiated when lipid particles containing cholesterol and other fats enter blood vessels where they become modified and lead to an inflammatory response in the blood vessel. This is associated with the induction of a variety of growth factors and matrix degrading enzymes that can eventually lead to a rupture on the inner surface of the blood vessel and to a myocardial infarction. Although many of the genes that are activated during vascular inflammation are known, the earliest steps that are required for the initiation of this process are still largely unknown. One set of key regulators of the expression of genes within blood vessels is transcription factors. These factors can serve as master switches for activating whole sets of genes. One of the transcription factors that is known to be activated during vascular inflammation is nuclear factor kappa B(NF-kB).

We have recently identified another transcription factor of the Ets family that is activated in vascular smooth muscle cells and endothelial cells in response to inflammatory stimuli. This factor, ESE-1 is not present in quiescent vascular cells, but is markedly upregulated in response to inflammatory cytokines. We have identified that this factor can interact with the transcription factor NF-kB to regulate the expression of the nitric oxide synthase gene. In a mouse model of bacterial sepsis, associated with acute vascular inflammation we found that the expression of ESE-1 was upregulated and correlated with the induction of nitric oxide synthase 2(NOS2) the inducible form of nitric oxide synthase.

Another mediator of vascular inflammation is Angiotensin II (Ang II). In more recent studies we have identified the prototypic ETS factor, Ets-1, as a critical mediator of Ang II-medidated vascular inflammation. Some of the downstream targets of Ets-1 include MCP-1, VCAM-1, and p47phox. Ets-1 may therefore be not only a critical mediator of vascular inflammation and remodeling in atherosclerosis but also in the setting of hypertension.