Endothelial cells are unique in their ability to switch from a "differentiated" (non-dividing, non-invasive) to a relatively "undifferentiated" (invasive and highly mitotic) phenotype during the process of blood vessel formation or angiogenesis. We are intrigued by this plasticity and our research efforts are guided towards understanding the molecular mechanisms involved in the regulation of endothelial gene expression. It is hoped that understanding the regulation of this switch will teach us lessons about differentiation pathways in general. Under this umbrella, the major focus of the laboratory has been the dissection of genetic programs involved in the formation and involution of blood vessels during development and in pathological conditions. 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.
Milde, F., Lauw, S. Koumoutsakos, P., and Iruela-Arispe, M.L., "The mouse retina in 3D: quantification of vascular growth and remodeling", Integrative Biology, (2013) [link].
Turlo, K.A., Scapa, J., Bagher, P., Jones, A.W., Feil, R., Korthuis, R.J., Segal, S.S., Iruela-Arispe, M.L., "Beta1-Integrin is essential for vasoregulation and smooth muscle survival In Vivo", Arterioscler Thromb Vasc Biol, 33 (10): 2325-2335 (2013) .
Iruela-Arispe, M.L., Beitel, G.J., "Tubulogenesis", Development, 140 (14): 2851-2855 (2013) .
Goddard, L.M., Ton, A.M., Org, T., Mikkola, H.K., Iruela-Arispe, M.L., "Selective suppression of endothelial cytokine production by progesterone receptor", Vascul. Pharmacol, 59 (1-2): 36-43 (2013) .
Janzen, D.M., Rosales, M.A., Paik, D.Y., Lee, D.S., Smith, D.A., Witte, O.N., Iruela-Arispe, M.L., Memarzadeh, S., "Progesterone receptor signaling in the microenvironment of endometrial cancer influences its response to hormonal therapy", Cancer Res, 73 (15): 4697-4710 (2013) .
Roodhart, J.M.L., He, H., Daenen, L.G.M., Monvoisin, A., Barber, C., van Amersfoort, M., Hofmann, J.J., Radtke, F., Lane, T.F., Voest, E.E., Iruela-Arispe, M.L., "Notch1 regulates angio-supportive bone-marrow-derived cells in mice: relevance to chemoresistance", Blood, 122 (1): 143-153 (2013) .
Baer, C., Squadrito, M.L., Iruela-Arispe, M.L., De Palma, M., "Reciprocal interactions between endothelial cells and macrophages in angiogenic vascular niches", Exp Cell Res, 319 (11): 1626-1634 (2013) .
Cristofaro, B., Shi, Y., Faria, M., Suchting, S., Leroyer, A.S., Trindade, A., Duarte, A., Zovein, A.C., Iruela-Arispe, M.L., Nih, L.R., Kubis, N., Henrion, D., Loufrani, L., Todiras, M., Schleifenbaum, J., Gollasch, M., Zhuang, Z.W., Simons, M., Eichmann, A., le Noble, F., "Dll4-Notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models", Development, 140 : 1720-1729 (2013) .
Goddard, L.M., Iruela-Arispe, M.L., "Cellular and molecular regulation of vascular permeability", Thromb. Haemost, 109 (3): 407-415 (2013) .
Defalco, T., Saraswathula, A., Briot, A., Iruela-Arispe, M.L., Capel, B., "Testosterone levels influence mouse fetal leydig cell progenitors through Notch signaling", Biol. Reprod, 88 (4): 1-12 (2013) .