Flow control in our vessels: vascular valves make sure there is no way back

Bazigou, Eleni; Mäkinen, Taija

doi:10.1007/s00018-012-1110-6

Cited by 114 publications

(113 citation statements)

References 75 publications

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“…23 Four different stages of valve development have been previously defined. 7,8 Figure 3A illustrates these valve maturation stages on the basis of Prox1 and CD31 costaining. Stage I is marked by the appearance of cell clusters expressing high levels of the transcription factor Prox1 at sites of developing valves.…”

Section: Bmp9 Is Required For Lymphatic Valve Formation In Mesentericmentioning

confidence: 99%

“…Foxc2 cooperates with Prox1 to control Connexin37 (Cx37) expression and to activate NFATc1/ Calcineurin signaling. 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.…”

mentioning

confidence: 99%

“…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%

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

Levet

Ciais

Merdzhanova

et al. 2013

Blood

127

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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Section: Bmp9 Is Required For Lymphatic Valve Formation In Mesentericmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Levet

Ciais

Merdzhanova

et al. 2013

Blood

127

111

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“…Lymphatic valves are composed of 2 intraluminal leaflets, each of which is formed by 2 layers of lymphatic ECs (LECs) separated by an extracellular matrix-rich core (5). The genetic and molecular program that underlies lymphatic valve formation has been recently revealed by studies of humans with primary lymphedema syndromes and mutant mice (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Lymph flow regulates collecting lymphatic vessel maturation in vivo

Sweet¹,

Jiménez²,

Chang³

et al. 2015

J. Clin. Invest.

162

197

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“…Therefore, lymph fluid within the large caliber lymphatic vessels can move in a retrograde manner. To prevent backflow of lymph, large caliber lymphatic vessels have lymphatic valves alongside the lymphatic wall, similar to the valves found in the large veins (Bazigou and Makinen, 2013). Excessive interstitial fluid is returned to blood circulation= îá~= subclavian veins and thoracic ducts which complete the lymphatic circulation.…”

Section: Lymphatic System: a Brief Overviewmentioning

confidence: 95%

A Tale of Two Models: Mouse and Zebrafish as Complementary Models for Lymphatic Studies

Kim¹,

Jin²

2014

Molecules and Cells

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Lymphatic vessels provide essential roles in maintaining fluid homeostasis and lipid absorption. Dysfunctions of the lymphatic vessels lead to debilitating pathological conditions, collectively known as lymphedema. In addition, lymphatic vessels are a critical moderator for the onset and progression of diverse human diseases including metastatic cancer and obesity. Despite their clinical importance, there is no currently effective pharmacological therapy to regulate functions of lymphatic vessels. Recent efforts to manipulate the Vascular Endothelial Growth Factor-C (VEGFC) pathway, which is arguably the most important signaling pathway regulating lymphatic endothelial cells, to alleviate lymphedema yielded largely mixed results, necessitating identification of new targetable signaling pathways for therapeutic intervention for lymphedema. Zebrafish, a relatively new model system to investigate lymphatic biology, appears to be an ideal model to identify novel therapeutic targets for lymphatic biology. In this review, we will provide an overview of our current understanding of the lymphatic vessels in vertebrates, and discuss zebrafish as a promising in vivo model to study lymphatic vessels.

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Flow control in our vessels: vascular valves make sure there is no way back

Cited by 114 publications

References 75 publications

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

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

Lymph flow regulates collecting lymphatic vessel maturation in vivo

A Tale of Two Models: Mouse and Zebrafish as Complementary Models for Lymphatic Studies

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