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Despite definite genetic evidence for key critical roles of Transforming Growth Factor (TGF)- Bone Morphogenic Protein (BMP) signaling for cardiovascular pathophysiology, thus far, there is still substantial controversy on the exact role of TGF-β/BMP in endothelial cells.
The research in my lab is mainly focused on understanding the role of TGF-β/BMP signaling path¬way in maintaining cardiovascular stability and homeostasis.
Mutations or dysregulation of TGF-β/BMP signaling pathway leads to vascular dysfunction in multiple vascular disorders including arterio-venous malformations (AVM), a clinical manifestation of Human Hereditary Hemorrhagic Telangiectasia (HHT) vascular disorder.
We recently discovered that in murine models of HHT, AVM formation is potentiated by blood flow and it is exclusively a pathogenic feature of BMP9 and BMP10 signaling through Activin like kinase 1 (ALK1) and Endoglin (ENG) receptors, and that SMAD4 acts as an essential effector in AVM pathogenesis (Ola et al., 2016; Lee, Chong, Ola et al., 2018; Ola et al., 2018). Deciphering the cellular and molecular mechanisms of how and why these vascular malformations form, will shed light into the exact role of TGF-β/BMP signaling in maintaining vascular stability and also will shed fundamental insight into the one of the least well and most controversial vascular signaling pathways. Our approach may pave the way towards novel mechanism-based therapeutic avenues to interfere with vascular dysfunction in HHT patients but also in other multiple disease states.
- Zhang F, Zarkada G, Han J, Li J, Dubrac A, Ola R, Genet G, Boyé K, Michon P, Künzel S, Camporez JP, Singh AK, Fong GH, Simons M, Tso P, Hernando CF, Shulman GI, Sessa WC, Eichmann A. Lacteal junction zippering protects against diet-induced obesity. Science. 2018; 361:599-603.
- Ola R, Künzel SH, Zhang F, Genet G, Chakraborty R, Fragner LP, Martin K, Sessa W, Dubrac A, Eichmann A. SMAD4 prevents flow induced arterial-venous malformations by inhibiting Casein Kinase 2. Circulation. 2018; 138:2379-2394.
- Ola R, Dubrac A, Han J, Fang JS, Zhang F, Larrivée B, Lee M, Urarte AA, Kraehling JR, Genet G, Hirschi KK, Sessa WC, Canals V, Graupera M, Yan M, Young LH, Oh SP, Eichmann A. PI3 Kinase inhibition improves vascular malformations in mouse models of Hereditary Hemorrhagic Telangiectasia. Nat. Commun. 2016; 7, 13650
- Lee HW,* Chong D,*, Ola R,* Dunworth WP, Meadows S, Ka J, Kaartinen V, Qyang Y, Cleaver O, Bautch V, Eichmann A, Jin SW. Distinct requirement of Alk2/ACVR1 and Alk3/BMPR1A in bone morphogenetic protein induced retinal angiogenesis. Arterioscler Thromb Vasc Biol. 2017; 37:657-663.
- Baeyens N,* Larrivée B,* Ola R, Hayward B, Dubrac A, Huang B, Ross TD, Coon B, Tsarfati M, Tong H, Eichmann A, Schwartz MA. Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia (HHT). J Cell Biol. 2016; 214:807-16.
Experimental Pharmacology Mannheim (EPM)
European Center for Angioscience (ECAS)
Medical Faculty Mannheim Heidelberg University
68167 Mannheim Germany