In Detail

Dr. Jeffrey Wigle is a developmental biologist who is studying how homeobox transcription factors control vascular growth during both embryonic development and during disease progression. Since many of the growth pathways used by fetal blood vessels are re-utilized in adults during disease, we can better understand disease processes by determining how the vessels grow during embryonic development. Dr. Wigle’s laboratory is studying the genes that control the growth of blood vessels (Meox1/Meox2) and that control the growth of lymphatic vessels (Prox1).

The lymphatic vasculature is a thin-walled, permeable system that functions to re-absorb protein rich extracellular fluid and returns this fluid to the circulatory system. Disruption of the lymphatic vasculature results in the accumulation of extracellular fluid and leads to diseases known as lymphedemas. Primary lymphedemas arise from a genetic cause and can vary in their onset and severity. In Canada, secondary lymphedema is a common, painful side effect that occurs when lymphatic nodes and vessels are destroyed during breast cancer therapy. In cancer, metastatic cells can enter the lymphatic circulation and escape the site of the original tumour. The degree of lymphatic vascularization has been correlated in both animal models and human studies with the tendency of tumour cells to spread. Regulating lymphatic growth represents a novel therapy target for the treatment of lymphedema or metastatic tumours. In Prox1 knockout mice, it has previously been demonstrated that the cells, which would normally become lymphatic endothelial cells, instead became blood endothelial cells. One of the goals of his research is to determine how Prox1 functions as a cell fate switch and thus regulates lymphatic vessel growth. By determining what genes are regulated by Prox1 directly and what genes are indirectly regulated, he will determine how Prox1 regulates the growth of lymphatic vessels.
Dr. Wigle’s work in establishing how Prox1 can regulate the cell fate choices made by endothelial cells during development will lead to better ways of regulating lymphatic growth during disease states and embryonic development.

Meox1/Meox2 are homeobox genes that are expressed early in the developing embryo. Meox2 (also known as Gax) was shown to be downregulated at both the mRNA and protein levels when vascular smooth muscle cells (VSMCs) are stimulated to proliferate with growth factors.Over expression of Meox2 protein halts VSMC growth by blocking proliferation and inducing cell death (apoptosis). In vivo, these effects lead to decreased vessel blockage (restenosis) in rodent models of balloon angioplasty. Recently, Meox2 expression was shown to be decreased in endothelial cells derived from blood vessels of Alzheimer disease patients and was required to maintain the ability of the endothelial cells to grow. Increased Meox2 expression has also been associated with diseases of accelerated ageing. In cell culture, Meox2 induces premature ageing (senescence) of cells. Dr. Wigle and his laboratory are determining the molecular mechanisms used by Meox2 and Meox1 to regulate VSMC and endothelial cell growth and death.

Northcott, J.M., Yeganeh, A., Taylor, C.G., Zahradka, P., Wigle, J.T. Adipokines and the cardiovascular system: mechanisms mediating health and disease. Can. J. Physiol. and Pharm. In press 2012.

Douville, J.M., Cheung, D.Y., Herbert, K.L., Moffatt,T., and Wigle, J.T. Mechanisms of MEOX1 and MEOX2 regulation of the cyclin dependent kinase inhibitors p21CIP1/WAF1 and p16INK4a in vascular endothelial cells. PLoS One 6(12):e29099, 2011.

Baxter,S.A., Bocangel,P., Cheung,D.Y., Kim,H.K., Zhang, S., Douville, J.M., Jangamreddy, J., Herbert,K., Eisenstat,D.D., and Wigle, J.T. Regulation of the lymphatic endothelial cell cycle by the PROX1 homeodomain protein. Biochim Biophys Acta. 1813:201-12, 2011.

Guo, J., Massaeli, H., Xu, X., Jia, Z., Wigle, J.T., Mesaeli, N., and Zhang, S. Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines. Journal of Clinical Investigation 119: 2745–2757, 2009.

Wigle, J.T., Harvey, N., Detmar, M., Lagutina, I., Grosveld, G., Gunn, M.D., Jackson, D.G., and Oliver, G. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J. 21: 1505-1513, 2002

Wigle, J.T. and Oliver, G. Prox1 function is required for the development of the murine lymphatic system. Cell 98: 769-778, 1999

Wigle, J.T., Chowdhury, K., Gruss, P., and Oliver, G. Prox1 function is crucial for mouse lens-fibre elongation.
Nature Genetics 21: 318-322, 1999

Manitoba Research Chair, Manitoba Health Research Council

New Investigator Award, Canadian Institutes of Health Research

New Investigator Award, Heart and Stroke Foundation of Canada

Canadian Institutes of Health Research Centennial Post Doctoral Fellowship