TY - JOUR
T1 - Mutations in EPHB4 cause human venous valve aplasia
T2 - Venous valve aplasia
AU - Lyons, Oliver
AU - Walker, James
AU - Seet, Christopher
AU - Ikram, Mohammed
AU - Kuchta, Adam
AU - Arnold, Andrew
AU - Hernandez-Vasquez, Magda
AU - Frye, Maika
AU - Vizcay-Barrena, Gema
AU - Fleck, Roland
AU - Patel, Ashish
AU - Padayachee, Soundrie
AU - Mortimer, Peter
AU - Jeffery, Steve
AU - Berland, Siren
AU - Mansour, Sahar
AU - Ostergaard, Pia
AU - Makinen, Taija
AU - Modarai, Bijan
AU - Saha, Prakash
AU - Smith, Alberto
N1 - Funding Information:
OL was funded by Academy of Medical Sciences Starter Grant for Clinical Lecturers (SGL016\1019), British Heart Foundation Centre of Research Excellence Travel Grant, and the Medical Research Council (G1000327).
Publisher Copyright:
© 2021, Lyons et al.
PY - 2021/9/22
Y1 - 2021/9/22
N2 - Venous valve (VV) failure causes chronic venous insufficiency, but the molecular regulation of valve development is poorly understood. A primary lymphatic anomaly, caused by mutations in the receptor tyrosine kinase EPHB4, was recently described, with these patients also presenting with venous insufficiency. Whether the venous anomalies are the result of an effect on VVs is not known. VV formation requires complex “organization” of valve-forming endothelial cells, including their reorientation perpendicular to the direction of blood flow. Using quantitative ultrasound, we identified substantial VV aplasia and deep venous reflux in patients with mutations in EPHB4. We used a GFP reporter in mice to study expression of its ligand, ephrinB2, and analyzed developmental phenotypes after conditional deletion of floxed Ephb4 and Efnb2 alleles. EphB4 and ephrinB2 expression patterns were dynamically regulated around organizing valve-forming cells. Efnb2 deletion disrupted the normal endothelial expression patterns of the gap junction proteins connexin37 and connexin43 (both required for normal valve development) around reorientating valve-forming cells and produced deficient valve-forming cell elongation, reorientation, polarity, and proliferation. Ephb4 was also required for valve-forming cell organization and subsequent growth of the valve leaflets. These results uncover a potentially novel cause of primary human VV aplasia.
AB - Venous valve (VV) failure causes chronic venous insufficiency, but the molecular regulation of valve development is poorly understood. A primary lymphatic anomaly, caused by mutations in the receptor tyrosine kinase EPHB4, was recently described, with these patients also presenting with venous insufficiency. Whether the venous anomalies are the result of an effect on VVs is not known. VV formation requires complex “organization” of valve-forming endothelial cells, including their reorientation perpendicular to the direction of blood flow. Using quantitative ultrasound, we identified substantial VV aplasia and deep venous reflux in patients with mutations in EPHB4. We used a GFP reporter in mice to study expression of its ligand, ephrinB2, and analyzed developmental phenotypes after conditional deletion of floxed Ephb4 and Efnb2 alleles. EphB4 and ephrinB2 expression patterns were dynamically regulated around organizing valve-forming cells. Efnb2 deletion disrupted the normal endothelial expression patterns of the gap junction proteins connexin37 and connexin43 (both required for normal valve development) around reorientating valve-forming cells and produced deficient valve-forming cell elongation, reorientation, polarity, and proliferation. Ephb4 was also required for valve-forming cell organization and subsequent growth of the valve leaflets. These results uncover a potentially novel cause of primary human VV aplasia.
KW - venous valves
KW - venous disease
KW - Developmental
UR - http://www.scopus.com/inward/record.url?scp=85115964573&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.140952
DO - 10.1172/jci.insight.140952
M3 - Article
SN - 2379-3708
VL - 6
SP - 1
EP - 57
JO - JCI Insight
JF - JCI Insight
IS - 18
M1 - e140952
ER -