In the projects related to developmental angiogenesis, our models include the murine mammary gland and the chicken embryo. The mammary gland provides us with an excellent platform in which to study the expansion and regression of the vasculature associated with the physiological changes of this organ. The chicken embryo enables us to study the formation and remodeling of the vasculature during normal development. Using these two models we search for genes involved in vascular morphogenesis and ask funtional/mechanistic questions using genetics (transgenics and knock-outs in the case of the mouse) and molecular biology (transfection or chicken embryos using electroporation). By perturbing gene expression we hoped to further dissect the molecular pathways that guide vascular formation and remodeling.
A second focus of the lab has been to identify novel angiogenesis inhibitors. Evolution of several pathologies, including the growth of tumors, requires formation of new blood vessels. Blockade of these new blood vessels had been extremely effective in the restriction of tumor growth and suppression of metastasis. Therefore, the identification of novel, tumor-vascular specific, and non-toxic inhibitors has become a major focus of several academic and biotechnology groups. Using the anti-angiogenic region of thrombospondin-1 we have cloned and characterized two novel inhibitors METH-1 (also known as ADAMTS-1) and METH-2 (also known as ADAMTS-8). METH-1 and 2 are able to effectively suppress proliferation of new capillaries and in xenograph assays inhibit the growth of tumors. Both molecules are secreted matrix metalloproteases with disintegrin and thrombospondin motifs. We have invested a great effort in the full characterization and in understanding the mechanisms of action of these molecules. Projects include structure/function analysis of each of the domains: generation of transgenics and knock-ins, identification of substrates / natural inhibitors, and understanding regulation of gene expression.
The effect of steroid hormones, in particular progesterone, on vascular networks in vivo is another focus of the lab. We have found that progesterone inhibits endothelial cell proliferation and have remarkable effects in vascular permeability. Determination of the signaling pathways that result in these events and their biological relevance are major research efforts on this project.
Sunshine H, Iruela-Arispe ML., "Membrane lipids and cell signaling", 28 (5): 408-413 (2017).
Mintet E, Lavigne J, Paget V, Tarlet G, Buard V, Guipaud O, Sabourin JC, Iruela-Arispe ML, Milliat F, Francois A., "Endothelial Hey2 deletion reduces endothelial-to-mesenchymal transition and mitigates radiation proctitis in mice", 7 (1): (2017).
Youssef, K., Jarenwattananon, N., Archer, B., Mack, J., Iruela-Arispe, M.L., Bouchard, L., "4-D flow control in porous scaffolds: Toward a next generation of bioreactors", IEEE Trans Biomed Eng 64 (1): 61-69 (2017).
Toullec, A., Valerie, B., Rannou, E., Tarlet, G., Guipaud, O., Robine, S., Iruela-Arispe, L.M., Francois, A., Milliat, F., "HIF-1? deletion in the endothelium, but not in the epithelium, protects from radiation-induced enteritis", Cellular and Molecular Gastroenterology and 5 (1): (2017).
Guihard, P.J., Yao, J., Blazquez-Medela, A.M., Iruela-Arispe, L., Bostrom, K.I., Yao, Y., "Endothelial-Mesenchymal Transition in Vascular Calcification of Ins2Akita/+ Mice", PLoS ONE 11 (12): (2016).
Shirali, A.S., McDonald, A.I., Mack, J.J., Iruela-Arispe, M.L., "Reproducible arterial denudation injury by infrarenal abdominal aortic clamping in a murine model", J Vis Exp (2016).
He, H., Mack, J.J., Guc, E., Warren, C.M., Squadrito, M.L., Kilarski, A.A., Baer, C., Freshman, R.D., MacDonald, A.I., Ziyad, S., Swartz, M.A., De Palma, M., Iruela-Arispe, M.L., "Perivascular macrophages limit permeability", ATVB 36: 2203-2212 (2016).
Briot, A., Bouloumie, A., Iruela-Arispe, M.L., "Notch, lipids, and endothelial cells", Curr. Opin. Lipidol 27 (5): 513-520 (2016).
Inkeles, M.S., Teles, R.M., Pouldar, D., Andrade, P.R., Madigan, C.A., Lopez, D., Ambrose, M., Noursadeghi, M., Sarno, E.N., Rea, T.H., Ochoa, M.T., Iruela-Arispe, M.L., Swindell, W.R., Ottenhoff, T.H., Geluk, A., Bloom, B.R., Pellegrini, M., Modlin, R.L., "Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy", JCI Insight 1 (15): (2016).
Uebelhoer, M., Iruela-Arispe, M.L., "Cross-talk between signaling and metabolism in the vasculature", Vasc. Pharmacol 83: 4-9 (2016).
Zovein, A.C., Iruela-Arispe, M.L., "Chapter 8 - Angiogenesis", In: Fetal and Neonatal Physiology, 2-Vols., 5th Edition 85-89 (2016).
Briot, A., Civelek, M., Seki, A., Hoi, K., Mack, J.J., Lee, S.D., Kim, J., Hong, C., Yu, J., Fishbein, G.A., Vakili, L., Fogelman A.M., Fishbein, M.C., Lusis, A.J., Tontonoz, P., Navab, M., Berliner, J.A., Iruela-Arispe, M.L., "Endothelial NOTCH1 is suppressed by circulating lipids and antagonizes inflammation during atherosclerosis", J Exp Med 212 (12): 2147-2163 (2015).
Hernandez-Garcia, R., Iruela-Arispe, M.L., Reyes-Cruz, G., Vazquez-Prado, J., "Endothelial RhoGEFs: A systematic analysis of their expression profiles in VEGF-stimulated and tumor endothelial cells", Vasc. Pharmcol 74: 60-72 (2015).
Moughon, D., He, H., Schokrpur, S., Jiang, Z.K., Jaqoob, M., David, J., Lin, C., Iruela-Arispe, M.L., Dorigo, O., Wu, L., "Macrophage blockade using CSF1R inhibitors reverses the vascular leakage underlying malignant ascites in late-stage epithelial ovarian cancer", Cancer Res 75: 4742-4752 (2015).
Rannou, E., Francois, A., Toullec, A., Guipaud, O., Buard, V., Tarlet, G., Jaillet, C., Iruela-Arispe, M.L., Benderitter, M., Sabourin, J.C., Milliat, F., "In vivo evidence for an endothelium-dependent mechanism in radiation-induced normal tissue injury", Sci Rep 5: (2015).