cAMP-dependent protein kinase A (PKA) regulates angiogenesis by modulating tip cell behavior in a Notch-independent manner
cAMP-dependent protein kinase A (PKA) regulates angiogenesis by modulating tip cell behavior in a Notch-independent manner
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DOI：
10.1242/dev.134767
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发表时间：
2016-10-01
期刊：
影响因子：
4.6
通讯作者：
Gerhardt, Holger
中科院分区：
文献类型：
--
作者：
Nedvetsky, Pavel I.;Zhao, Xiaocheng;Gerhardt, Holger
cAMP依赖性蛋白激酶A（PKA）是一种广泛表达的丝氨酸/苏氨酸激酶，其调节多种细胞功能。在这里，我们表明，内皮PKA活性是必不可少的血管发育，特别是调节从萌芽到稳定的新生血管的过渡。内皮细胞特异性表达的显性阴性PKA抑制内皮PKA在小鼠中导致血管发育紊乱，出血和胚胎死亡在妊娠中期。在围产期视网膜血管生成过程中，PKA的抑制会导致尖端细胞数量增加，从而导致超增殖。在斑马鱼中，细胞自主PKA抑制也增加和维持内皮细胞运动，驱动细胞成为尖端细胞。尽管PKA抑制的这些作用高度地使人联想到Notch抑制作用，但是我们的数据表明PKA和Notch独立地调节尖端和柄细胞的形成和行为。
cAMP-dependent protein kinase A (PKA) is a ubiquitously expressed serine/threonine kinase that regulates a variety of cellular functions. Here, we demonstrate that endothelial PKA activity is essential for vascular development, specifically regulating the transition from sprouting to stabilization of nascent vessels. Inhibition of endothelial PKA by endothelial cell-specific expression of dominant-negative PKA in mice led to perturbed vascular development, hemorrhage and embryonic lethality at mid-gestation. During perinatal retinal angiogenesis, inhibition of PKA resulted in hypersprouting as a result of increased numbers of tip cells. In zebrafish, cell autonomous PKA inhibition also increased and sustained endothelial cell motility, driving cells to become tip cells. Although these effects of PKA inhibition were highly reminiscent of Notch inhibition effects, our data demonstrate that PKA and Notch independently regulate tip and stalk cell formation and behavior.