title: Carbohydrate-binding protein CLEC14A regulates VEGFR-2- and VEGFR-3-dependent signals during angiogenesis and lymphangiogenesis.
abstract: Controlled angiogenesis and lymphangiogenesis are essential for tissue development, function, and repair. However, aberrant neovascularization is an essential pathogenic mechanism in many human diseases, including diseases involving tumor growth and survival. Here, we have demonstrated that mice deficient in C-type lectin family 14 member A (CLEC14A) display enhanced angiogenic sprouting and hemorrhage as well as enlarged jugular lymph sacs and lymphatic vessels. CLEC14A formed a complex with VEGFR-3 in endothelial cells (ECs), and CLEC14A KO resulted in a marked reduction in VEGFR-3 that was concomitant with increases in VEGFR-2 expression and downstream signaling. Implanted tumor growth was profoundly reduced in CLEC14A-KO mice compared with that seen in WT littermates, but tumor-bearing CLEC14A-KO mice died sooner. Tumors in CLEC14A-KO mice had increased numbers of nonfunctional blood vessels and severe hemorrhaging. Blockade of VEGFR-2 signaling suppressed these vascular abnormalities and enhanced the survival of tumor-bearing CLEC14A-KO mice. We conclude that CLEC14A acts in vascular homeostasis by fine-tuning VEGFR-2 and VEGFR-3 signaling in ECs, suggesting its relevance in the pathogenesis of angiogenesis-related human disorders.
authors.forename: Sungwoon
authors.initials: S
authors.lastname: Lee
authors.forename: Seung-Sik
authors.initials: SS
authors.lastname: Rho
authors.forename: Hyojin
authors.initials: H
authors.lastname: Park
authors.forename: Jeong Ae
authors.initials: JA
authors.lastname: Park
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
mesh_terms: D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D042583:Lymphangiogenesis; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism*
chemical_list: C555817:Clec14a protein, mouse; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3