Hypoxia-induced downregulation of Sema3a and CXCL12/CXCR4 regulate the formation of the coronary artery stem at the proper site.
Hypoxia-induced downregulation of Sema3a and CXCL12/CXCR4 regulate the formation of the coronary artery stem at the proper site.
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DOI：
10.1016/j.yjmcc.2020.08.001
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发表时间：
2020-08
影响因子：
5
通讯作者：
Mayu Narematsu;Tatsuya Kamimura;T. Yamagishi;Y. Nakajima
中科院分区：
文献类型：
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作者：
Mayu Narematsu;Tatsuya Kamimura;T. Yamagishi;Y. Nakajima
背景：在冠状动脉干形成的过程中，来自于枢干周围内皮祖细胞池的内皮链进入主动脉壁。血管内皮生长因子（vegf）以及CXCL12/CXCR4信号被认为在冠状动脉干的形成中发挥作用。然而，调节内皮链如何侵入主动脉的机制尚不清楚。方法和结果免疫组化结果显示，在内皮链形成之前，Sema3a在大动脉周围内皮祖细胞中高表达。当内皮链侵入主动脉时，内皮链中的Sema3a下调，而CXCR4上调。原位杂交显示，与肺动脉相比，cxcl12在主动脉壁高表达。利用禽类胚胎心脏，我们建立了两种类型的内皮渗透实验，其中冠状动脉内皮链在培养中优先侵入主动脉。Sema3a阻断肽诱导过多内皮链穿透肺动脉，而重组Sema3a抑制内皮链的形成。在培养的冠状动脉内皮祖细胞中，重组VEGF蛋白诱导了cxcr4阳性的内皮链，这些内皮链能够被cxcl12浸没的珠粒吸引。单偶氮罗丹明检测到卵细胞的主动脉/主动脉下区以缺氧为主，在培养过程中，缺氧可下调Sema3a的表达。结论主动脉区缺氧可下调Sema3a的表达，从而增强VEGF活性，诱导cxcr4阳性内皮链的形成，这些内皮链随后被吸引到xcl12阳性的主动脉壁连接主动脉腔。
BackgroundDuring the formation of the coronary artery stem, endothelial strands from the endothelial progenitor pool surrounding the conotruncus penetrate into the aortic wall. Vascular endothelial growth factors (VEGFs) as well as CXCL12/CXCR4 signaling are thought to play a role in the formation of the coronary stem. However, the mechanisms regulating how endothelial strands exclusively invade into the aorta remain unknown.Methods and resultsImmunohistochemistry showed that before the formation of endothelial strands, Sema3a was highly expressed in endothelial progenitors surrounding the great arteries. At the onset of/during invasion of endothelial strands into the aorta, Sema3a was downregulated and CXCR4 was upregulated in the endothelial strands.In situhybridization showed thatCxcl12was highly expressed in the aortic wall compared with in the pulmonary artery. Using avian embryonic hearts, we established two types of endothelial penetration assay, in which coronary endothelial strands preferentially invaded into the aorta in culture. Sema3a blocking peptide induced an excess number of endothelial strands penetrating into the pulmonary artery, whereas recombinant Sema3a inhibited the formation of endothelial strands. In cultured coronary endothelial progenitors, recombinant VEGF protein induced CXCR4-positive endothelial strands, which were capable of being attracted by CXCL12-impregnated beads. Monoazo rhodamine detected that hypoxia was predominant in aortic/subaortic regionin ovoand hypoxic condition downregulated the expression of Sema3a in culture.ConclusionResults suggested that hypoxia in the aortic region downregulates the expression of Sema3a, thereby enhancing VEGF activity to induce the formation of CXCR4-positive endothelial strands, which are subsequently attracted into theCxcl12-positive aortic wall to connect the aortic lumen.