Vascular and Liver Homeostasis in Juvenile Mice Require Endothelial Cyclic AMP-Dependent Protein Kinase A.
Vascular and Liver Homeostasis in Juvenile Mice Require Endothelial Cyclic AMP-Dependent Protein Kinase A.
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DOI：
10.3390/ijms231911419
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发表时间：
2022-09-27
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
在血管发育过程中，内皮cAMP依赖性蛋白激酶A（PKA）通过控制尖端细胞的数量来调节血管生成，并且PKA抑制导致过度的血管生成。内皮PKA的这种作用是否仅限于胚胎和新生儿的发育，还是以后血管稳态所需尚不清楚。在这里，我们表明，围产期（出生后的日子P1-P3）的后期（P28-P32）抑制内皮PKA使用显性负PKA的控制下表达的内皮特异性Cdh 5-CreERT 2重组酶（dnPKAiEC小鼠）导致严重的皮下水肿，低白蛋白血症，低血糖症和过早死亡。这些变化伴随着脂肪垫局部血管的增生和皮下淋巴管的继发性增大。最值得注意的是，内皮PKA抑制引起肝脏血管系统的急剧紊乱。肝脏变化与肝异生减少相关，而肝脏白蛋白生成似乎不受影响，低白蛋白血症是由于向肝内渗漏增加所致。有趣的是，dnPKA仅在使用Prox 1-CreERT 2的细胞中表达不产生表型。同样，仅使用Vegfr 3-CreERT 2的内皮亚群中的镶嵌表达不足以诱导水肿或低血糖。尖端细胞标志物ESM 1的表达增加表明PKA的抑制诱导了肝脏中的血管生成反应，尽管组织来源的促血管生成因子和抗血管生成因子没有变化。这些数据表明，内皮PKA是内皮细胞激活的看门人，不仅在发展中，而且在成人的稳态，防止异常的血管生成程序的再激活。
During vascular development, endothelial cAMP-dependent protein kinase A (PKA) regulates angiogenesis by controlling the number of tip cells, and PKA inhibition leads to excessive angiogenesis. Whether this role of endothelial PKA is restricted to embryonic and neonatal development or is also required for vascular homeostasis later on is unknown. Here, we show that perinatal (postnatal days P1–P3) of later (P28–P32) inhibition of endothelial PKA using dominant-negative PKA expressed under the control of endothelial-specific Cdh5-CreERT2 recombinase (dnPKAiEC mice) leads to severe subcutaneous edema, hypoalbuminemia, hypoglycemia and premature death. These changes were accompanied by the local hypersprouting of blood vessels in fat pads and the secondary enlargement of subcutaneous lymphatic vessels. Most noticeably, endothelial PKA inhibition caused a dramatic disorganization of the liver vasculature. Hepatic changes correlated with decreased gluconeogenesis, while liver albumin production seems to be unaffected and hypoalbuminemia is rather a result of increased leakage into the interstitium. Interestingly, the expression of dnPKA only in lymphatics using Prox1-CreERT2 produced no phenotype. Likewise, the mosaic expression in only endothelial subpopulations using Vegfr3-CreERT2 was insufficient to induce edema or hypoglycemia. Increased expression of the tip cell marker ESM1 indicated that the inhibition of PKA induced an angiogenic response in the liver, although tissue derived pro- and anti-angiogenic factors were unchanged. These data indicate that endothelial PKA is a gatekeeper of endothelial cell activation not only in development but also in adult homeostasis, preventing the aberrant reactivation of the angiogenic program.
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影响因子：
3.3
作者：
FARRUKH, IS;GURTNER, GH;MICHAEL, JR
通讯作者：
MICHAEL, JR
影响因子：
4.6
作者：
Nedvetsky, Pavel I.;Zhao, Xiaocheng;Gerhardt, Holger
通讯作者：
Gerhardt, Holger
影响因子：
4.1
作者：
HORTON, RA;CEPPI, ED;TITHERADGE, MA
通讯作者：
TITHERADGE, MA
影响因子：
82.9
作者：
Bakre, MM;Zhu, YH;Varner, JA
通讯作者：
Varner, JA
影响因子：
1.2
作者：
Cogger, Victoria C.;O'Reilly, Jennifer N.;Le Couteur, David G.
通讯作者：
Le Couteur, David G.