Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 37, Issue 9, Pages 1710-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.117.308226
Keywords
angiogenesis modulating agents; mice; myc; semaphorins; thrombospondins; yolk sac
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Funding
- Italian Association for Cancer Research (AIRC) [15645, 13016, 16702, 10133, 12182]
- FPRC-ONLUS grant MIUR Vaschetto - 5 per mille MIUR
- FPRC 5xmille Ministero Salute
- Swiss National Science Foundation, Sinergia grant [CRSII3 160742/1]
- Fondi di Ricerca Locale, University of Turin
- Fondo Investimenti per la Ricerca di Base [RBAP11BYNP]
- European Community-FP7 [318035]
- Fondazione Umberto Veronesi
- Telethon Italy [GGP09175]
- Associazione Augusto per la Vita
- Swiss National Science Foundation (SNF) [CRSII3_160742] Funding Source: Swiss National Science Foundation (SNF)
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Objective-Molecular pathways governing blood vessel patterning are vital to vertebrate development. Because of their ability to counteract proangiogenic factors, antiangiogenic secreted Sema3 (class 3 semaphorins) control embryonic vascular morphogenesis. However, if and how Sema3 may play a role in the control of extraembryonic vascular development is presently unknown. Approach and Results-By characterizing genetically modified mice, here, we show that surprisingly Sema3F acts instead as a selective extraembryonic, but not intraembryonic proangiogenic cue. Both in vivo and in vitro, in visceral yolk sac epithelial cells, Sema3F signals to inhibit the phosphorylation-dependent degradation of Myc, a transcription factor that drives the expression of proangiogenic genes, such as the microRNA cluster 17/92. In Sema3f-null yolk sacs, the transcription of Myc-regulated microRNA 17/92 cluster members is impaired, and the synthesis of Myc and microRNA 17/92 foremost antiangiogenic target Thbs 1 (thrombospondin 1) is increased, whereas Vegf (vascular endothelial growth factor) signaling is inhibited in yolk sac endothelial cells. Consistently, exogenous recombinant Sema3F inhibits the phosphorylation-dependent degradation of Myc and the synthesis of Thbsl in mouse F9 teratocarcinoma stem cells that were in vitro differentiated in visceral yolk sac epithelial cells. Sema3f-mice placentas are also highly anemic and abnormally vascularized. Conclusions-Sema3F functions as an unconventional Sema3 that promotes extraembryonic angiogenesis by inhibiting the Myc-regulated synthesis of Thbs 1 in visceral yolk sac epithelial cells.
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