- Investigating vascular integrity in inflammation and cardiovascular disease.
- Elucidating cytoskeletal-mediated cell-cell junction regulation.
- Understanding how mechanical forces control endothelial adhesions.
Endothelial mechanotransduction in inflammation and vascular disease
Within blood vessels, endothelial cell-cell and cell-matrix adhesions are crucial to preserve barrier function, and these adhesions are tightly controlled during vascular development, angiogenesis and transendothelial migration of inflammatory and tumor cells. Endothelial cells respond to mechanical changes in the vasculature by a complex array of intracellular biochemical and structural changes. This mechanotransduction response include signals that promote, but also signals that protect against, monolayer permeability. Excessive extracellular matrix (ECM) stiffening during aging disturbs this balance and causes permeability and inflammation in vascular disease and acute respiratory distress syndrome. In addition, increased stiffness is an early sign of vascular damage after chemo- or radiotherapy. Surprisingly, the underlying molecular events that control stiffness-induced mechanotransduction remain elusive. To achieve this we study the endothelium in the physiological setting of the vascular wall and recently discovered that differences in wall stiffness of human arterial and venous vessels modulate endothelial adhesions. See also our publications in Circulation Research 2015 and Arteriosclerosis, Thrombosis and Vascular Biology 2014.
Molecular changes at the VE-cadherin complex that regulate endothelial integrity
The integrity of endothelial cell-cell adhesions is regulated in space and time during angiogenesis and inflammation. To achieve this, VE-cadherin, the central component of endothelial cell-cell adhesions, is targeted by many major vascular signaling pathways. However, the molecular effects of angiogenic or inflammatory signals on the VE-cadherin complex, that may explain the tight spatiotemporal control of cell-cell adhesion, remain largely unclear. It is known that local organization of the actin cytoskeleton plays an important role in regulating the VE-cadherin complex. See our publications in Cellular and Molecular Life Sciences 2017, Nature Communications 2016, Journal of Cell Science 2013 and Journal of Cell Biology 2012 for details. Identifying the molecular changes at the VE-cadherin-based adhesion that occur upon cytoskeletal-dependent remodeling, and unveiling their dynamics at cell-cell junctions in response to signals will be key to understand the control of endothelial cell-cell adhesion during angiogenesis and inflammation. Our previous publications and current preliminary data show that the molecular composition of endothelial cell-cell adhesions in response to permeability signals (VEGF and thrombin), is different from that of mature/linear adhesions. Vinculin and other proteins specifically associate with the active subset of VE-cadherin-adhesions (Focal Adherens Junctions) that is linked to, and dependent on, the contractile actin cytoskeleton. We are elucidating the molecular regulation of the VE-cadherin complex.