Integrin binding site within the gC1q domain orchestrates EMILIN-1-induced lymphangiogenesis

Alessandra Capuano, Eliana Pivetta, Francesca Baldissera, Giulia Bosisio, Bruna Wassermann, Francesco Bucciotti, Alfonso Colombatti, Patrizia Sabatelli, Roberto Doliana, Paola Spessotto

Research output: Contribution to journalArticle

Abstract

Lymphatic vessels (LVs) play a pivotal role in the control of tissue homeostasis and also have emerged as important regulators of immunity, inflammation and tumor metastasis. EMILIN-1 is the first ECM protein identified as a structural modulator of the growth and maintenance of LV; accordingly, Emilin1−/− mice display lymphatic morphological alterations leading to functional defects as mild lymphedema, leakage and compromised lymph drainage. Many EMILIN-1 functions are exerted by the binding of its gC1q domain with the E933 residue of α4 and α9β1 integrins. To investigate the specific regulatory role of this domain on lymphangiogenesis, we generated a transgenic mouse model expressing an E933A-mutated EMILIN-1 (E1-E933A), unable to interact with α4 or α9 integrin. The mutant resulted in abnormal LV architecture with dense, tortuous and irregular networks; moreover, the number of anchoring filaments was reduced and collector valves had aberrant narrowed structures. E933A mutation also affected lymphatic function in lymphangiography assays and made the transgenic mice more prone to lymph node metastases. The finding that the gC1q/integrin interaction is crucial for a correct lymphangiogenesis response was confirmed and reinforced by functional in vitro tubulogenesis assays. In addition, ex vivo thoracic-duct ring assays revealed that E1-E933A-derived lymphatic endothelial cells had a severe reduction in sprouting capacity and were unable to organize into capillary-like structures. All these data provide evidence that the novel “regulatory structural” role of EMILIN-1 in the lymphangiogenic process is played by the integrin binding site within its gC1q domain.

Original languageEnglish
JournalMatrix Biology
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Lymphangiogenesis
Integrins
Lymphatic Vessels
Binding Sites
Transgenic Mice
Neoplasm Metastasis
Thoracic Duct
Lymphography
Lymphedema
Lymph
Drainage
Immunity
Homeostasis
Endothelial Cells
Lymph Nodes
Maintenance
Inflammation
Mutation
Growth
Neoplasms

Keywords

  • Extracellular matrix
  • Integrin
  • Lymph node metastasis
  • Lymphangiogenesis
  • Lymphatic endothelial cells

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Integrin binding site within the gC1q domain orchestrates EMILIN-1-induced lymphangiogenesis. / Capuano, Alessandra; Pivetta, Eliana; Baldissera, Francesca; Bosisio, Giulia; Wassermann, Bruna; Bucciotti, Francesco; Colombatti, Alfonso; Sabatelli, Patrizia; Doliana, Roberto; Spessotto, Paola.

In: Matrix Biology, 01.01.2018.

Research output: Contribution to journalArticle

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AU - Capuano, Alessandra

AU - Pivetta, Eliana

AU - Baldissera, Francesca

AU - Bosisio, Giulia

AU - Wassermann, Bruna

AU - Bucciotti, Francesco

AU - Colombatti, Alfonso

AU - Sabatelli, Patrizia

AU - Doliana, Roberto

AU - Spessotto, Paola

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N2 - Lymphatic vessels (LVs) play a pivotal role in the control of tissue homeostasis and also have emerged as important regulators of immunity, inflammation and tumor metastasis. EMILIN-1 is the first ECM protein identified as a structural modulator of the growth and maintenance of LV; accordingly, Emilin1−/− mice display lymphatic morphological alterations leading to functional defects as mild lymphedema, leakage and compromised lymph drainage. Many EMILIN-1 functions are exerted by the binding of its gC1q domain with the E933 residue of α4 and α9β1 integrins. To investigate the specific regulatory role of this domain on lymphangiogenesis, we generated a transgenic mouse model expressing an E933A-mutated EMILIN-1 (E1-E933A), unable to interact with α4 or α9 integrin. The mutant resulted in abnormal LV architecture with dense, tortuous and irregular networks; moreover, the number of anchoring filaments was reduced and collector valves had aberrant narrowed structures. E933A mutation also affected lymphatic function in lymphangiography assays and made the transgenic mice more prone to lymph node metastases. The finding that the gC1q/integrin interaction is crucial for a correct lymphangiogenesis response was confirmed and reinforced by functional in vitro tubulogenesis assays. In addition, ex vivo thoracic-duct ring assays revealed that E1-E933A-derived lymphatic endothelial cells had a severe reduction in sprouting capacity and were unable to organize into capillary-like structures. All these data provide evidence that the novel “regulatory structural” role of EMILIN-1 in the lymphangiogenic process is played by the integrin binding site within its gC1q domain.

AB - Lymphatic vessels (LVs) play a pivotal role in the control of tissue homeostasis and also have emerged as important regulators of immunity, inflammation and tumor metastasis. EMILIN-1 is the first ECM protein identified as a structural modulator of the growth and maintenance of LV; accordingly, Emilin1−/− mice display lymphatic morphological alterations leading to functional defects as mild lymphedema, leakage and compromised lymph drainage. Many EMILIN-1 functions are exerted by the binding of its gC1q domain with the E933 residue of α4 and α9β1 integrins. To investigate the specific regulatory role of this domain on lymphangiogenesis, we generated a transgenic mouse model expressing an E933A-mutated EMILIN-1 (E1-E933A), unable to interact with α4 or α9 integrin. The mutant resulted in abnormal LV architecture with dense, tortuous and irregular networks; moreover, the number of anchoring filaments was reduced and collector valves had aberrant narrowed structures. E933A mutation also affected lymphatic function in lymphangiography assays and made the transgenic mice more prone to lymph node metastases. The finding that the gC1q/integrin interaction is crucial for a correct lymphangiogenesis response was confirmed and reinforced by functional in vitro tubulogenesis assays. In addition, ex vivo thoracic-duct ring assays revealed that E1-E933A-derived lymphatic endothelial cells had a severe reduction in sprouting capacity and were unable to organize into capillary-like structures. All these data provide evidence that the novel “regulatory structural” role of EMILIN-1 in the lymphangiogenic process is played by the integrin binding site within its gC1q domain.

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KW - Lymphangiogenesis

KW - Lymphatic endothelial cells

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