Abstract
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.
Highlights
Unidirectional blood flow requires functional venous valves (VVs), which are widely distributed throughout human veins and venules, predominantly in vessels less than 100 μm in diameter [1]
Clinical studies have suggested a link between venous reflux and some primary lymphedemas, and we have previously shown striking human VV disease in patients with primary lymphedema caused by mutations in FOXC2 (MIM 602402) and GJC2 (MIM 608803; refs. 11, 17–20)
Pathogenic mutations in EPHB4 were recently described in 2 families with primary lymphatic-related fetal hydrops (LRFH), with autosomal dominant inheritance [21]
Summary
Unidirectional blood flow requires functional venous valves (VVs), which are widely distributed throughout human veins and venules, predominantly in vessels less than 100 μm in diameter [1]. Lower limb VVs are typically bicuspid and situated just upstream of the confluence with a tributary [1, 2] Failure of these valves is the central feature of the venous reflux that is seen in up to 40% of adults [3, 4], congenital VV aplasia has been identified [5,6,7,8]. Our understanding of the molecular mechanisms of VV embryological development, maintenance after formation, and failure in disease is limited, and there are few therapeutic options to treat VV dysfunction [3, 11,12,13,14,15,16] Elucidating these mechanisms and understanding how their dysfunction may lead to VV failure could facilitate the development of novel therapies
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
