The integrity of the vascular wall is dependent on proper cell-cell contact between endothelial cells. This cell-cell contact is mediated by VE (Vascular Endothelial)-cadherin (CD144), a calcium-dependent homotypic adhesion molecule. The adhesive function of VE-cadherin is regulated in a dynamic fashion by both extracellular stimuli (VEGF, TNF, thrombin, as well as vessel wall stiffness, etc) and intracellular signalling. For the regulation of VE-cadherin, its link to the actin cytoskeleton, via its intracellular domain, is essential.
To increase our molecular insights in these events, our group focuses on the regulation of actin dynamics in the context of endothelial integrity. We are particularly interested in the role and regulation of Rho-like GTPases. We use a range of in vitro approaches including biochemical assays, high resolution imaging and electrical resistance measurements of endothelial monolayers. Recently, we identified several ubiquitin ligases that specifically regulate Rho proteins and, in this way, control endothelial integrity.
Related research activities aim to link our molecular studies in endothelial cells to human disease. In collaboration with our colleagues from the clinic, we focus specifically on hypertensive disorders and cardiac disease related to diastolic dysfunction.
1. Kovačević I, Sakaue T, Majoleé J, Pronk MC, Maekawa M, Geerts D, Fernandez-Borja M, Higashiyama S, Hordijk PL. The Cullin-3-Rbx1-KCTD10 complex controls endothelial barrier function via K63 ubiquitination of RhoB. J Cell Biol. 2018 Mar 5;217(3):1015-1032.
2. Reinhard NR, Mastop M, Yin T, Wu Y, Bosma EK, Gadella TWJ Jr, Goedhart J, Hordijk PL. The balance between Gα(i)-Cdc42/Rac and Gα(1)(2)/(1)(3)-RhoA pathways determines endothelial barrier regulation by sphingosine-1-phosphate. Mol Biol Cell. 2017 Nov 7;28(23):3371-3382.
3. Dorland YL, Malinova TS, van Stalborch AM, Grieve AG, van Geemen D, Jansen NS, de Kreuk BJ, Nawaz K, Kole J, Geerts D, Musters RJ, de Rooij J, Hordijk PL, Huveneers S. The F-BAR protein pacsin2 inhibits asymmetric VE-cadherin internalization from tensile adherens junctions. Nat Commun. 2016 Jul 15;7:12210.
4. Reinhard NR, van Helden SF, Anthony EC, Yin T, Wu YI, Goedhart J, Gadella TW, Hordijk PL. Spatiotemporal analysis of RhoA/B/C activation in primary human endothelial cells. Sci Rep. 2016 6:25502.
5. Huveneers S, Daemen MJ, Hordijk PL. Between Rho(k) and a hard place: the relation between vessel wall stiffness, endothelial contractility, and cardiovascular disease. Circ Res. 2015 ;116(5):895-908.