The Vascular Biology of Scleroderma

Stephen Schwartz, MD, PhD
University of Washington, Seattle

Project Summary:

Dr. Schwartz’s laboratory is working to understand the vascular injury that occurs in scleroderma (SSc). They have determined that capillaries (the smallest caliber blood vessels) disappear in scleroderma. This vasculopathy seems to be a very early step in the disease, perhaps leading to the connective tissue changes (fibrosis) or even to the events that initiate the autoimmune response. Through various studies, including molecular studies looking for certain proteins in the cells of the blood vessels (histology), microarrays that quantify the expression levels of all the genes in certain cells, and analyses of proteins present in the blood, Dr. Schwartz and his colleagues have identified specific vascular proteins having differential expression in scleroderma and normal vessels. In particular, Dr. Schwartz and his colleagues have focused on VE-cadherin. They believe that VE-cadherin, a molecule typically seen on the surface of endothelial cells and one that is required for the appropriate development of the small blood vessels, may be lost in SSc blood vessels. This may be a critical factor in the loss of capillaries seen in scleroderma. They are also developing a cell culture assay to explore mechanisms of blood vessel loss in scleroderma.

Research Update:

Dr. Schwartz’s laboratory was to further confirm that IFNa (interferon alpha) together with VEGF (a critical factor for blood vessel growth) has dramatic and negative effects in standard blood vessel formation experiments done in culture. In the classic aortic ring experiment, there is a proliferation of smooth muscle cells and an excess of myofibroblasts. These cell types are typical of scleroderma vascular tissue but not of normal vascular tissue. This new observation suggests that IFNa might be playing a key role in SSc. This would be a novel and important finding. Also, it would put scleroderma in a more analogous position to the dysregulation observed in lupus. In lupus, IFNa has been implicated as a key negative factor and there are ongoing clinical trials to assess agents that absorb the IFNa in the blood and body of lupus patients.

Further investigation is underway to confirm the presence of the RGS5 (regulator of G-protein signaling-5) receptor on the surface of the smooth muscle cells. RGS5 appears to be over expressed in SSc vessels and disappears in at least one case of “cure” from HDIT (high dose immuno-ablative therapy) followed by stem cell transplant. It was further shown that RGS5 expression is inhibited by PDGF (another growth factor that is critical in vessel growth and maintenance).

A vital set of hypotheses has emerged from all these disparate observations: 1) Does IFNa drive the loss of vessels? If so, is this process similar or different from that seen in lupus?; 2) Does RGS5 act as a repressor of hedgehog signaling? Hedgehog is a critical factor for the survival and renewal of most stem cell populations for example, MSCs (mesenchymal stem cells) and the stem cell that is critical in blood vessel formation. So, if RGS5 is up-regulated, then the stem cells cannot effect their normal repair; and 3) Is the process in SSc fundamentally the same as or different from the vessel destruction seen in other diseases—especially transplant arteriosclerosis?

What this project means for people with scleroderma:

It may be possible to specifically activate endothelial cells in SSc patients to re-express VE-cadherin. Alternatively, it may be possible to block the process that leads to shutting off the VE-cadherin expression. Or, it may be possible to block IFNa. If effective, the normalized endothelial cells would support the regeneration of capillaries in scleroderma patients.

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