An Unexpected Role of Semaphorin3A–Neuropilin-1 Signaling in Lymphatic Vessel Maturation and Valve Formation

Jurisic, Giorgia; Hajjami, Hélène Maby–El; Karaman, Sinem; Ochsenbein, Alexandra M.; Alitalo, Annamari; Siddiqui, Shoib Sarwar; Ochoa, Carlos; Petrova, Tatiana V.; Detmar, Michael

doi:10.1161/circresaha.112.269399

Cited by 123 publications

(98 citation statements)

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“…Because Sema3A was reported to repel pericytes during lymphatic vessel development (Bouvree et al, 2012;Jurisic et al, 2012), we investigated whether pericyte coverage around tip cells was altered in P7 Sema3A-cECKO pups. NG2-stained pericytes did not co-stain for Nrp1 and showed no grossly changed coverage in Sema3A-cECKO retinas compared with Sema3A-WT littermates (Fig.…”

Section: Resultsmentioning

confidence: 99%

Endothelial cell-derived semaphorin 3A inhibits filopodia formation by blood vascular tip cells

Ochsenbein¹,

Karaman²,

Proulx³

et al. 2016

Journal of Cell Science

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Vascular endothelial growth factor (VEGF)-A is a well-known major chemoattractant driver of angiogenesis -the formation of new blood vessels from pre-existing ones. However, the repellent factors that fine-tune this angiogenic process remain poorly characterized. We investigated the expression and functional role of endothelial cellderived semaphorin 3A (Sema3A) in retinal angiogenesis, using genetic mouse models. We found Sema3a mRNA expression in the ganglion cell layer and the presence of Sema3A protein on larger blood vessels and at the growing front of blood vessels in neonatal retinas. The Sema3A receptors neuropilin-1 and plexin-A1 were expressed by retinal blood vessels. To study the endothelial cellspecific role of Sema3A, we generated endothelial cell-specific Sema3A knockout mouse strains by constitutive or inducible vascular endothelial cadherin-Cre-mediated gene disruption. We found that in neonatal retinas of these mice, both the number and the length of tip cell filopodia were significantly increased and the leading edge growth pattern was irregular. Retinal explant experiments showed that recombinant Sema3A significantly decreased VEGF-A-induced filopodia formation. Endothelial cell-specific knockout of Sema3A had no impact on blood vessel density or skin vascular leakage in adult mice. These findings indicate that endothelial cell-derived Sema3A exerts repelling functions on VEGF-A-induced tip cell filopodia and that a lack of this signaling cannot be rescued by paracrine sources of Sema3A.

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Section: Resultsmentioning

confidence: 99%

Endothelial cell-derived semaphorin 3A inhibits filopodia formation by blood vascular tip cells

Ochsenbein¹,

Karaman²,

Proulx³

et al. 2016

Journal of Cell Science

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“…Dashed box in left-hand panel indicates area depicted at higher magnification in the other schematics. REVIEW Development 140 (9) Jurisic et al, 2012). In addition, SEMA3A has been proposed to maintain valve regions as 'smooth muscle cell-free' zones by repelling smooth muscle cells that express the NRP1 receptor away from valves (Bouvrée et al, 2012;Jurisic et al, 2012).…”

Section: Lymphatic Valve Formationmentioning

confidence: 99%

“…REVIEW Development 140 (9) Jurisic et al, 2012). In addition, SEMA3A has been proposed to maintain valve regions as 'smooth muscle cell-free' zones by repelling smooth muscle cells that express the NRP1 receptor away from valves (Bouvrée et al, 2012;Jurisic et al, 2012). Valveforming cells exhibit a distinct molecular and morphological profile compared with neighbouring non-valve LECs; they have elevated levels of the junctional markers PECAM1 and VE-cadherin, reduced expression of LYVE1 and NRP2, and are enriched in specific connexins [CX37, CX43 (GJA1) and CX47 (GJC2)] (Kanady et al, 2011;Bouvrée et al, 2012;Sabine et al, 2012).…”

Section: Lymphatic Valve Formationmentioning

confidence: 99%

Getting out and about: the emergence and morphogenesis of the vertebrate lymphatic vasculature

et al. 2013

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SummaryThe lymphatic vascular system develops from the pre-existing blood vasculature of the vertebrate embryo. New insights into lymphatic vascular development have recently been achieved with the use of alternative model systems, new molecular tools, novel imaging technologies and growing interest in the role of lymphatic vessels in human disorders. The signals and cellular mechanisms that facilitate the emergence of lymphatic endothelial cells from veins, guide migration through the embryonic environment, mediate interactions with neighbouring tissues and control vessel maturation are beginning to emerge. Here, we review the most recent advances in lymphatic vascular development, with a major focus on mouse and zebrafish model systems.

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“…7,8 Other molecular regulators such as EphrinB2, integrin a9, Connexin43 (Cx43), Semaphorin3a, and Neuropilin1 (Nrp-1) have been reported to be important for either lymphatic valve formation, elongation of lymphatic valve leaflets, or valve maturation. 5,[8][9][10][11][12] However, still not much is known concerning the extracellular factors that govern valve development.The activin receptor-like kinase 1 (ALK1) is a type 1 receptor of the transforming growth factor-b family that is specifically expressed on endothelial cells. 13 We have previously shown that bone morphogenetic protein 9 (BMP9) and BMP10 bind with high affinity to ALK1.…”

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confidence: 99%

Bone morphogenetic protein 9 (BMP9) controls lymphatic vessel maturation and valve formation

Levet

Ciais

Merdzhanova

et al. 2013

Blood

125

111

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Key Points• BMP9 is required for lymphatic valve formation.• Mice deficient in Bmp9 exhibit reduction in lymphatic draining efficiency.Lymphatic vessels are critical for the maintenance of tissue fluid homeostasis and their dysfunction contributes to several human diseases. The activin receptor-like kinase 1 (ALK1) is a transforming growth factor-b family type 1 receptor that is expressed on both blood and lymphatic endothelial cells (LECs). Its high-affinity ligand, bone morphogenetic protein 9 (BMP9), has been shown to be critical for retinal angiogenesis. The aim of this work was to investigate whether BMP9 could play a role in lymphatic development. We found that Bmp9 deficiency in mice causes abnormal lymphatic development. Bmp9-knockout (KO) pups presented hyperplastic mesenteric collecting vessels that maintained LYVE-1 expression. In accordance with this result, we found that BMP9 inhibited LYVE-1 expression in LECs in an ALK1-dependent manner. Bmp9-KO pups also presented a significant reduction in the number and in the maturation of mesenteric lymphatic valves at embryonic day 18.5 and at postnatal days 0 and 4. Interestingly, the expression of several genes known to be involved in valve formation (Foxc2, Connexin37, EphrinB2, and Neuropilin1) was upregulated by BMP9 in LECS. Finally, we demonstrated that Bmp9-KO neonates and adult mice had decreased lymphatic draining efficiency. These data identify BMP9 as an important extracellular regulator in the maturation of the lymphatic vascular network affecting valve development and lymphatic vessel function. (Blood. 2013;122(4):598-607) IntroductionThe lymphatic vasculature is essential for the maintenance of normal fluid balance and for the immune response. It consists of a network of vessels that drain protein-rich lymph from the extracellular space back to the blood circulation, which absorbs dietary fatty acids and is involved in the traffic of immune cells.1 Lymphatic vessels may also serve as a conduit to lymph nodes and thereby participate in systemic metastasis of cancer cells. Hypoplasia, disruption or dysfunction of the lymphatic vessels, impair the ability of the lymphatic vasculature to collect and transport fluids and lead to lymphedema. 1,2The mammalian lymphatic system has been shown to originate from embryonic veins. Lymphatic vessel development starts at embryonic days (E) 9.5 to 10.5 in mice. After formation of the primary lymph sacs, further expansion leads to the formation of a primary lymphatic vascular plexus that, through subsequent remodeling and maturation, will provide a hierarchical network of lymphatic capillaries and lymphatic collecting vessels.1,3 During this vessel specification, maturation of collecting vessels is accompanied by the downregulation of lymphatic marker molecules such as LYVE-1, the acquisition of partial smooth muscle cell coverage, and the formation of intraluminal valves. [4][5][6] Lymphatic valves are essential components that ensure unidirectional lymph flow. They develop from E15.5 to early postnatal d...

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An Unexpected Role of Semaphorin3A–Neuropilin-1 Signaling in Lymphatic Vessel Maturation and Valve Formation

Cited by 123 publications

References 42 publications

Endothelial cell-derived semaphorin 3A inhibits filopodia formation by blood vascular tip cells

Endothelial cell-derived semaphorin 3A inhibits filopodia formation by blood vascular tip cells

Getting out and about: the emergence and morphogenesis of the vertebrate lymphatic vasculature

Bone morphogenetic protein 9 (BMP9) controls lymphatic vessel maturation and valve formation

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