Axon Guidance Molecules in Vascular Patterning

Adams, Ralf H.; Eichmann, Anne

doi:10.1101/cshperspect.a001875

Cited by 347 publications

(304 citation statements)

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“…In contrast, there are very few known developmentally regulated, naturally occurring anti-angiogenic molecules, which include platelet factor 4 [4], thrombospondin-1 [5], and pigment epithelium-derived factor [6], whose precise mechanism of action is not fully understood. In this regard, emerging evidence suggests that proteins involved in transmitting axonal guidance cues, including members of the netrin, slit, eph and semaphorin families, also play a critical role in blood vessel guidance during physiological and pathological blood vessel development [7,8]. In this review, we summarize the current knowledge on semaphorin family proteins in angiogenesis, with an emphasis on semaphorin-regulated anti-angiogenic signaling circuitries in endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

2011

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Angiogenesis, the formation of new blood vessels from preexisting vasculature, is essential for many physiological processes, and aberrant angiogenesis contributes to some of the most prevalent human diseases, including cancer. Angiogenesis is controlled by delicate balance between pro-and anti-angiogenic signals. While pro-angiogenic signaling has been extensively investigated, how developmentally regulated, naturally occurring anti-angiogenic molecules prevent the excessive growth of vascular and lymphatic vessels is still poorly understood. In this review, we summarize the current knowledge on how semaphorins and their receptors, plexins and neuropilins, control normal and pathological angiogenesis, with an emphasis on semaphorin-regulated anti-angiogenic signaling circuitries in vascular and lymphatic endothelial cells. This emerging body of information may afford the opportunity to develop novel anti-angiogenic therapeutic strategies.

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Section: Introductionmentioning

confidence: 99%

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

2011

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“…The ISVs appear to be connected to the CV after they form and navigate between somites using the same cues that guide axon growth cones. 12,16,17 Notably, although the vessel of origin for the ISV endothelium in mouse embryos remains controversial, these structures are already detected before the appearance of the first LEC progenitors in the CV. 8,17 To further characterize the relationship between ISVs and Prox1-expressing LECs, we took advantage of available Tie2Cre;COUP-TFII ϩ/f embryos in which COUP-TFII ϩ VECs can be visualized by ␤-gal staining after 1 copy of COUP-TFII is deleted without showing any obvious phenotype.…”

Section: Intersomitic Vessels Are a Newly Identified Source Of Prox1-mentioning

confidence: 99%

“…12,16,17 Notably, although the vessel of origin for the ISV endothelium in mouse embryos remains controversial, these structures are already detected before the appearance of the first LEC progenitors in the CV. 8,17 To further characterize the relationship between ISVs and Prox1-expressing LECs, we took advantage of available Tie2Cre;COUP-TFII ϩ/f embryos in which COUP-TFII ϩ VECs can be visualized by ␤-gal staining after 1 copy of COUP-TFII is deleted without showing any obvious phenotype. 10 Analysis of sagittal, frontal, and transverse sections revealed that Prox1-expressing LEC progenitors were not only present in the CV, but were also localized with COUP-TFII ϩ VECs inside all the ISVs at E10.5 ( Figure 2A-C arrowheads; supplemental Figure 1D-F arrowheads; n ϭ 3 embryos of each type of section).…”

Section: Intersomitic Vessels Are a Newly Identified Source Of Prox1-mentioning

confidence: 99%

“…It was previously shown that plexinD1 loss-of-function mutations in mice and zebrafish result in patterning defects of ISVs; these defects are not because of changes in EC proliferation. 12,17 In particular, analysis of PlexinD1 Ϫ/Ϫ mouse embryos revealed obvious alterations in the patterning of the ISVs as well as a general increase in the number of ISV branches at E10.5 (supplemental Figure 2). In agreement with our proposal that ISVs are also a source of LEC progenitors, in PlexinD1 Ϫ/Ϫ embryos we found Prox1 ϩ cells located in the ISVs branches as well as a general increase in the number of LEC progenitors in the mesenchyme surrounding the ISVs (supplemental Figure 2A-B arrowheads, C; n ϭ 3 embryos, *P Ͻ .05).…”

Section: Intersomitic Vessels Are a Newly Identified Source Of Prox1-mentioning

confidence: 99%

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Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos

Yang

García‐Verdugo

Soriano-Navarro

et al. 2012

Blood

198

196

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The lymphatic vasculature preserves tissue fluid balance by absorbing fluid and macromolecules and transporting them to the blood vessels for circulation. The stepwise process leading to the formation of the mammalian lymphatic vasculature starts by the expression of the gene Prox1 in a subpopulation of blood endothelial cells (BECs) on the cardinal vein (CV) at approximately E9.5. These Prox1-expressing lymphatic endothelial cells (LECs) will exit the CV to form lymph sacs, primitive structures from which the entire lymphatic network is derived. Until now, no conclusive information was available regarding the cellular processes by which these LEC progenitors exit the CV without compromising the vein's integrity. We determined that LECs leave the CV by an active budding mechanism. During this process, LEC progenitors are interconnected by VE-cadherin-expressing junctions. Surprisingly, we also found that Prox1-expressing LEC progenitors were present not only in the CV but also in the intersomitic vessels (ISVs). Furthermore, as LEC progenitors bud from the CV and ISVs into the surrounding mesenchyme, they begin expressing the lymphatic marker podoplanin, migrate away from the CV, and form the lymph sacs. Analyzing this process in Prox1-null embryos revealed that Prox1 activity is necessary for LEC progenitors to exit the CV. (Blood. 2012;120(11):2340-2348) IntroductionOur understanding of the genes and mechanisms controlling the development of the mammalian lymphatic vasculature has greatly advanced in the last decade. The results of targeted inactivation experiments in mice have identified 3 transcription factors (Prox1, Sox18, and COUP-TFII) as crucial regulators of early lymphatic endothelial cell (LEC) differentiation in mammals; their functional inactivation results in a complete lack of LECs and, therefore, of the entire lymphatic vasculature. [1][2][3][4] It is generally accepted that the initiation of Prox1 expression in a subpopulation of venous endothelial cells (VECs) in the wall of the mouse cardinal vein (CV) at around E9.5 is one of the earliest steps during mammalian lymphatic vasculature formation. We have previously shown that the embryonic veins are the unique source of the entire mammalian lymphatic vasculature by showing that Prox1-expressing LECs that exit the CV form the embryonic lymph sacs from which the entire lymphatic vasculature is eventually derived. 2,5 Although it is known that in mammals Vegfc signaling is required for LECs to exit the CV, 6 until now no conclusive data were available regarding the cellular mechanisms involved in this critical process. For instance, how do these endothelial cells (ECs) exit the CV? How is it that LECs leave the CV without disrupting the endothelial barrier? To address some of these important questions, we performed electron microscopy (EM) to visualize Prox1-expressing LEC progenitors leaving the CV. Results from these analyses determined that Prox1-expressing LEC progenitors leave the CV by budding and that the integrity of the CV is not compromi...

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“…However, it is crucial to point out that the growth of a functional vessel network requires the coordination of proangiogenic and antiangiogenic activities of ECs. 2,3,46,47 The current understanding of the sprouting process rests on the realization that the populations of ECs that compose sprouting vessels are heterogeneous in their angiogenic behavior and signaling: When stimulated by proangiogenic signals (eg, VEGF) only a subset of ECs acquires an explorative phenotype. These so called "tip cells" are located at the leading end of the vessel sprout and extend numerous filopodia toward the source of the angiogenic signal 46,47 ( Figure 1B).…”

Section: Foxos Are Essential Regulators Of Vascular Growthmentioning

confidence: 99%