Michelle Letarte

Our laboratory works primarily on a protein called endoglin that we discovered originally in childhood pre-B leukemic cells. Endoglin is however expressed primarily on the vascular endothelium and mutated in the vascular disease, Hereditary Haemorrhagic Telangiectasia type 1 (HHT1). The endothelium being the interface between the circulation and the tissues, it plays a critical role in leukocyte recruitment and control of infections and we need to ascertain the role of endoglin in these functions.

Our main objectives are to understand the function of endoglin and to characterize the endothelial cell pathways that are defective in HHT. We discovered endoglin and cloned the human and mouse genes and generated a mouse model of HHT1. HHT an autosomal dominant vascular disorder present in 1;8,000 individuals, and associated with frequent nosebleeds, mucocutaneous telangiectatic lesions and arteriovenous malformations often characterized by leukocyte infiltration and inflammation.

We have shown that haploinsufficiency is the underlying model of HHT, meaning that it is the reduced level of functional endoglin on the vascular endothelium that leads to disease and not interference by the mutated gene copy. The Endoglin (Eng) heterozygous mouse is therefore the disease model. The homozygous null mouse dies at mid-gestation with severe cardiovascular defects. We also work with the mouse model of HHT2, the Alk1 heterozygous mouse.

By imaging techniques we have demonstrated the presence of a truncated lung vasculature in adult Eng and Alk1 heterozygous mice. We have shown that endoglin and ALK1 interact with endothelial Nitric Oxide Synthase (eNOS), and are involved in regulating the production of the potent vasodilator NO. In fact, in HHT, eNOS activation is impaired and the enzyme produces superoxide instead of NO. Superoxide is implicated in many disorders. We have shown that an anti-oxidant can prevent the onset of adult lung phenotype when given orally starting a 3 weeks of age.

Using human and mouse endothelial cells, we study the pathways associated with endoglin and ALK1 and defective in disease. We have shown that endoglin is a co-receptor for ligands of the transforming growth factor beta (TGF-ß) superfamily. While in the plasma membrane, it binds TGF-ß in association with TGF-ß receptors I and II, which are serine/threonine kinases acting via Smad 2/3 proteins. Endothelial cells also possess an extra type I receptor, ALK1, which signals via Smad 1/5 proteins. More recently, we have been working on the BMP9, which was shown to be the true ligand for ALK1. Furthermore, BMP9 can bind to purified endoglin with high affinity, suggesting that it may be highly relevant to HHT pathobiology.

We have also been studying the role of a circulating form of endoglin, called sEng, which is increased in the serum of women with preeclampsia, a pregnancy related complication that affects 5% of births and causes maternal hypertension. We are studying the contribution of TGF-ß and BMP9 to this disease and how sEng can lead to systemic maternal hypertension.

We are testing the contribution of endoglin to inflammation, in a mouse model of inflammatory bowel disease. We have shown that Eng heterozygous mice progress to chronic colitis while normal mice recover after the acute phase. The chronic inflammation is associated with pathological angiogenesis and severity of disease. We are studying the relative contribution of the endothelial and immune cells to inflammation. We are also testing how anti-angiogenic therapy can attenuate chronic inflammation.

Our research team works on several aspects of endoglin from structure to function, in cells and animal models. We use a variety of molecular, cellular and immunological techniques to unravel the role of endoglin and ALK1 in normal and diseased vascular and immune systems.

Recent Publications

1. Pece-Barbara, N., Vera, S., Kathirkamathamby, K., Liebner, S., Di Guglielmo, G.M., Dejana, E., Wrana, J.L., Letarte, M. (2005) Endoglin null endothelial cells proliferate faster, and are more responsive to TGF-b1 with higher affinity receptors and an activated ALK1 pathway. J. Biol. Chem. 280:27800-27808.
2. Letarte, M., Voulgaraki, D., Hartherley, D., Foster-Cuevas, M., Saunders, N.J., and Barclay, N. (2005) Analysis of leukocyte membrane protein interactions using protein microarrays. BMC Biochem. 6:2 doi:10.1186/1471-2091-6-2.
3. Schmidt-Weber, C.B., Letarte, M., Kunzmann, S., Rückert, B., Bernabéu, C., Blaser, K. (2005) TGF-ß signaling of human T cell is modulated by the ancillary TGF-ß receptor endoglin. Int. Immunol. 7:921-30.
4. Toporsian M, Gros R, Kabir MG, Vera S, Govindaraju K, Eidelman DH, Husain M and Letarte, M. (2005) A role for endoglin in coupling eNOS activity and regulating vascular tone revealed in hereditary hemorrhagic telangiectasia. Circ. Res. 96: 684-92.
5. Jerkic, M., Rivas-Elena, J. V. Prieto, M., Rodríguez-Barbero, A., Santibanez, J. F., Pericacho, M., Arevalo, M., Vary, C. P. H., Bernabeu, C., Letarte, M., and López-Novoa, J. M. (2006) Endoglin regulates COX-2 expression and activity. Circ. Res. 99:248-256.
6. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE, Roberts D, D'Amore PA, Epstein FH, Sellke FW, Romero R, Sukhatme VP, Letarte M and Karumanchi SA. (2006) Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat. Med. 12: 642-649.
7. Abdalla SA and Letarte M. (2006) Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet 43: 97-110.
8. Prigoda, N.L., Savas, S., Abdalla, S.A., Piovesan, B., Rushlow, D., Vandezande, K., Zhang, E., Ozcelik, H., Gallie, B.L., Letarte, M. (2006) Hereditary haemorrhagic telangiectasia: Mutation detection, test sensitivity and novel mutations. J. Med. Genet. 43:722-8.
9. Thomas, B., Eyries, M., Montagne, K., Martin, S., Agrapart, M., Simerman-François, R., Letarte, M., Soubrier, F. (2007) Altered endothelial gene expression associated with hereditary haemorrhagic telangiectasia. Eur. J. Clin. Invest. 37:580-588.
10. Rudini, N., Felici, A., Giampietro, C., Lampugnani, M., Corada, M., Swirsding, K., Garrè, M., Liebner, S., Letarte, M., ten Dijke, P., Dejana, E. (2008) VE-cadherin is a critical endothelial regulator of TGF-ß signaling. EMBO J. 27: 993-1004.
11. Chen, Y., Hao, Q., Kim, H., Su, H., Letarte, M., Karumanchi, AS., Lawton, MT., Barbaro, NM., Yang, GY., and Young, William L.H (2009) Soluble endoglin modulates aberrant cerebral vascular remodeling. Ann. Neurol. 66:19-27.
12. Nomura-Kitabayashi, A., Anderson, G., Sleep, G., Mena, J., Karabegovic, A., Karamath, S., Letarte, M., and Puri, M. (2009) Endoglin is dispensable for angiogenesis, but required for endocardial cushion formation in the midgestation mouse embryo. Dev. Biol. 335:66-77.
13. Belik, J., Jerkic, M., McIntyre, B.A.S., Pan, J., Leen, J, Yu, L.X., Henkelman, R.M., Toporsian, M., and Letarte, M. (2009) Age-dependent endothelial nitric oxide synthase uncoupling in pulmonary arteries of endoglin heterozygous mice. Am. J. Pathol. Lung Cell Mol. Physiol. 297:L1170-L1178.
14. Toporsian, M., Jerkic, M., Zhou, Y.Q., Kabir, M.G., Yu, L.X., McIntyre, B.A.S., Davis, A., Wang, Y.J., Stewart, D.J., Belik, J., Husain, M., Henkelman, M., Letarte, M. (2010) Spontaneous adult-onset pulmonary arterial hypertension due to increased endothelial oxidative stress in a murine model of hereditary hemorrhagic telangiectasia. Arterioscler. Thromb.Vasc. Biol. 30:509-517.
15. Jerkic, M., Peter, M., Ardelean, D., Fine, M., Konerding, M., Letarte, M. (2010) Dextran sulfate sodium leads to chronic colitis and pathological angiogenesis in Endoglin heterozygous mice. Inflamm. Bowel. Dis. 16:1859-70.
16. Al-Saleh, S., John, P. R., Letarte, M., Faughnan, M.E., Belik, J., and Ratjen, F. (2011) Severe Symptomatic Liver Arteriovenous Malformations in Neonatal Hereditary Hemorrhagic Telangiectasia. Pediatrics. 127:e1615.
17. Jerkic, M., Kabir, M.G., Davies, A., Yu, L.X., McIntyre, B.A.S., Husain, N.W., Enomoto, M. Sotov, V., Husain, M., Henkelman, M., Belik, J. and Letarte, M. (2011) Pulmonary hypertension in adult Alk1 heterozygous mice is associated with oxidative stress. Cardiovasc. Res. (In press).