Stephan Huveneers

Vascular Microenvironment & Integrity

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Huveneers Lab

Associate Prof. Stephan Huveneers, PhD

Biosketch

Dr. Stephan Huveneers completed his PhD at the Netherlands Cancer Institute in 2008 and then did his postdoc at the Hubrecht Institute. In 2012, he started his research group at Sanquin Research and was recruited to the Amsterdam UMC in 2016 to embed his research lab in a cardiovascular biomedical research institute.

Blood vessels encounter forces derived from blood pressure, flow, and the vessel wall. Failure of the vascular endothelium to respond to forces affects barrier function and underlies vascular leakage in cardiovascular disease.

The Huveneers Lab investigates vascular integrity in inflammation and cardiovascular disease by elucidating cytoskeletal-mediated cell-cell junction regulation. The lab aims to understand how mechanical forces regulate endothelial cell adhesion. Their studies have resulted in the identification and unraveling of important molecular systems that control endothelial barrier function, angiogenesis and are involved in stiffness-related cardiovascular disease. The use of live fluorescence microscopy approaches is a key signature of their studies.

www.huveneerslab.eu

Huveneers Lab

News

Huveneers lab publishes about angiogenesis in Nature Communications

door Stephan Huveneers • 08 mrt., 2023

Researchers from the Huveneers lab at Amsterdam UMC, together with international collaborators from the Universities of Cologne and Barcelona, published their latests findings on dedicated molecular signals in angiogenesis in Nature Communications.

Huveneers Lab

Research

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. To date, 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. Local organization of the actin cytoskeleton plays an important role in regulating the VE-cadherin complex. Identifying the molecular changes at the VE-cadherin-based adhesion that occur upon cytoskeletal-dependent remodeling, and unveiling their dynamics at cell-cell junctions will be key to understand endothelial cell-cell adhesion during angiogenesis and inflammation. Our previous work and current preliminary data show that the molecular composition of remodeling endothelial cell-cell adhesions in response to vascular permeability signals, is different from that of mature adhesions. Vinculin, Pacsin2 and other proteins specifically associate with the active subset of VE-cadherin-adhesions (Focal Adherens Junctions) that is linked to the contractile actin cytoskeleton. See our publications in Cell Reports 2022, Nature Communications 2021, Trends in Cell Biology 2018, Nature Communications 2016, Journal of Cell Science 2013 and Journal of Cell Biology 2012 for details. We are currently elucidating the molecular regulation of the VE-cadherin complex at Adherens Junctions.

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Endothelial mechanotransduction in inflammation and vascular disease

Within blood vessels, endothelial cell-cell and cell-matrix adhesions are crucial to preserve barrier function. 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 biochemical and mechanical changes. This mechanotransduction response include signals that promote, but also signals that protect against, monolayer permeability. Excessive vessel stiffening during aging disturbs this balance and causes permeability and inflammation underlying the development of vascular disease. 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 previously discovered that differences in wall stiffness of human arterial and venous vessels modulate endothelial adhesions. See also our publications in for example ACS Nano 2019, Circulation Research 2015 and Arteriosclerosis, Thrombosis and Vascular Biology 2014.

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Huveneers Lab

The team

Stephan Huveneers

Principal Investigator

Annett de Haan

Technician

Aukie Hooglugt

PhD student

Vera Janssen

PhD student

Rianne Schoon

PhD student

Johanna Comes

PhD student

Matthijs Heijmans

MSc student

Sytske Poppen

BSc student

You?!

Stephan Huveneers

Publications

KEY PUBLICATIONS

# Shared first authors, * Shared last authors.

van der Stoel MM#, Kotini MP#, Schoon RM, Affolter M, Belting HG*, Huveneers S*. Vinculin strengthens the endothelial barrier during vascular development. VASCULAR BIOLOGY, 5(1):e220012, 2023.

Hooglugt A, Klatt O, Huveneers S. Vascular stiffening and endothelial dysfunction in atherosclerosis. CURRENT OPINION IN LIPIDOLOGY, 33(6):353-363, 2022.

Kotini MP#, van der Stoel MM#, Yin J, Han MK, Kirchmaier B, de Rooij J, Affolter M, Huveneers S*, HG Belting*. Vinculin controls endothelial cell junction dynamics during vascular lumen formation. CELL REPORTS, 39(2): 110658, 2022.

Malinova TS, Angulo-Urarte A, Nüchel J, Tauber M, van der Stoel MM, Janssen V, de Haan A, Groenen AG, Tebbens M, Graupera M, Plomann M, Huveneers S. A junctional PACSIN2/EHD4/MICAL-L1 complex coordinates VE-cadherin trafficking for endothelial migration and angiogenesis. NATURE COMMUNICATIONS, 12(1):2610, 2021.

Tan JME#, van der Stoel MM#, van den Berg M, van Loon NM, Moeton M, Scholl E, van der Wel NN, Kovačević I, Hordijk PL, Loregger A, Huveneers S*, Zelcer N*. The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting. CELL REPORTS. 32(5):107944, 2020.

Angulo-Urarte A, van der Wal T, Huveneers S. Cell-cell junctions as sensors and transducers of mechanical forces. BBA BIOMEMBRANES, 862(9):183316, 2020.

van der Stoel M, Schimmel L, Nawaz K, van Stalborch AM, de Haan A, Klaus-Bergmann A, Valent ET, Koenis DS, van Nieuw Amerongen GP, de Vries CJ, de Waard V, Gloerich M, van Buul JD, Huveneers S. DLC1 is a direct target of activated YAP/TAZ that drives collective migration and sprouting angiogenesis. JOURNAL OF CELL SCIENCE, 133(3). pii: jcs 239947, 2020.

Beldman TJ#, Malinova TS#, Desclos E, Grootemaat AE, Misiak ALS, van der Velden S, van Roomen CPAA, Beckers L, van Veen HA, Krawczyk PM, Hoebe RA, Sluimer JC, Neele AE, de Winther MPJ, van der Wel NN, Lutgens E, Mulder WJM, Huveneers S, Kluza E. Nanoparticle-Aided Characterization of Arterial Endothelial Architecture during Atherosclerosis Progression and Metabolic Therapy. ACS NANO, 13(12): 13759-13774, 2019.

Malinova TS, Huveneers S. Sensing of cytoskeletal forces by asymmetric adherens junctions. TRENDS CELL BIOL, 28(4):328-341, 2018.

Dorland YL*, Malinova TS*, van Stalborch AMD, Grieve AG, van Geemen D, Jansen NS, de Kreuk BJ, Nawaz K, Kole J, Geerts D, Musters RJP, de Rooij J, Hordijk PL, Huveneers S. The F-BAR protein pacsin2 inhibits asymmetric VE-cadherin internalization from tensile adherens junctions. NATURE COMMUNICATIONS, 7:12210, 2016.

Huveneers S, Daemen MJAP, Hordijk PL. Between Rho(k) and a hard place: the relation between vessel wall stiffness, endothelial contractility, and cardiovascular disease. CIRCULATION RESEARCH, 116 (5):895-908, 2015.

van Geemen D, Smeets MWJ, van Stalborch AMD, Woerdeman LAE, Daemen MJAP, Hordijk PL, Huveneers S. F-actin-anchored focal adhesions distinguish endothelial phenotypes of human arteries and veins. ARTERIOSCLEROSIS, THROMBOSIS & VASCULAR BIOLOGY;34 (9):2059-2067, 2014.

Huveneers S, Oldenburg J, Spanjaard E, van der Krogt G, Grigoriev I, Akhmanova A, Rehmann H, de Rooij J. Vinculin associates with endothelial VE-cadherin junctions to control force-dependent remodeling. JOURNAL OF CELL BIOLOGY, 196 (5):641-652, 2012.

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Medical Biochemistry