Functional Importance of a Proteoglycan Coreceptor in Pathologic Lymphangiogenesis

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http://hdl.handle.net/10138/165264

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Johns , S C , Yin , X , Jeltsch , M , Bishop , J R , Schuksz , M , El Ghazal , R , Wilcox-Adelman , S A , Alitalo , K & Fuster , M M 2016 , ' Functional Importance of a Proteoglycan Coreceptor in Pathologic Lymphangiogenesis ' , Circulation Research , vol. 119 , no. 2 , pp. 210-+ . https://doi.org/10.1161/CIRCRESAHA.116.308504

Title: Functional Importance of a Proteoglycan Coreceptor in Pathologic Lymphangiogenesis
Author: Johns, Scott C.; Yin, Xin; Jeltsch, Michael; Bishop, Joseph R.; Schuksz, Manuela; El Ghazal, Roland; Wilcox-Adelman, Sarah A.; Alitalo, Kari; Fuster, Mark M.
Contributor: University of Helsinki, Research Programs Unit
University of Helsinki, Research Programs Unit
Date: 2016-07-08
Language: eng
Number of pages: 24
Belongs to series: Circulation Research
ISSN: 0009-7330
URI: http://hdl.handle.net/10138/165264
Abstract: Rationale: Lymphatic vessel growth is mediated by major prolymphangiogenic factors, such as vascular endothelial growth factor (VEGF-C) and VEGF-D, among other endothelial effectors. Heparan sulfate is a linear polysaccharide expressed on proteoglycan core proteins on cell membranes and matrix, playing roles in angiogenesis, although little is known about any function(s) in lymphatic remodeling in vivo. Objective: To explore the genetic basis and mechanisms, whereby heparan sulfate proteoglycans mediate pathological lymphatic remodeling. Methods and Results: Lymphatic endothelial deficiency in the major heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1; involved in glycan-chain sulfation) was associated with reduced lymphangiogenesis in pathological models, including spontaneous neoplasia. Mouse mutants demonstrated tumor-associated lymphatic vessels with apoptotic nuclei. Mutant lymphatic endothelia demonstrated impaired mitogen (Erk) and survival (Akt) pathway signaling and reduced VEGF-C-mediated protection from starvation-induced apoptosis. Lymphatic endothelial-specific Ndst1 deficiency (in Ndst1(f/f)Prox1(+/CreERT2) mice) was sufficient to inhibit VEGF-C-dependent lymphangiogenesis. Lymphatic heparan sulfate deficiency reduced phosphorylation of the major lymphatic growth receptor VEGF receptor-3 in response to multiple VEGF-C species. Syndecan-4 was the dominantly expressed heparan sulfate proteoglycan in mouse lymphatic endothelia, and pathological lymphangiogenesis was impaired in Sdc4((-/-)) mice. On the lymphatic cell surface, VEGF-C induced robust association between syndecan-4 and VEGF receptor-3, which was sensitive to glycan disruption. Moreover, VEGF receptor-3 mitogen and survival signaling was reduced in the setting of Ndst1 or Sdc4 deficiency. Conclusions: These findings demonstrate the genetic importance of heparan sulfate and the major lymphatic proteoglycan syndecan-4 in pathological lymphatic remodeling. This may introduce novel future strategies to alter pathological lymphatic-vascular remodeling.
Subject: apoptosis
lymphangiogenesis
phosphorylation
proteoglycans
VEGF receptor
ENDOTHELIAL GROWTH-FACTOR
HEPARAN-SULFATE PROTEOGLYCANS
SQUAMOUS-CELL CARCINOMA
FACTOR-C
ACTIN REORGANIZATION
TUMOR-GROWTH
VEGF-C
ANGIOGENESIS
ACTIVATION
METASTASIS
3111 Biomedicine
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