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.
The authors declare no competing or financial interests.
Designed experiments: P.I.N., R.J.M., K.E.M. and H.G. Performed experiments: P.I.N., X.Z., T.M., I.M.A. and F.S. Analyzed the data: P.I.N., F.S., R.J.M. and H.G. Wrote the paper: P.I.N. and H.G.
This study was supported by grants from the Fonds voor Wetenschappelijk Onderzoek (FWO) [G.0742.15N to H.G]; the Else-Kröner-Fresenius-Stiftung [2014_A26 to H.G and P.I.N]; the European Research Council [ERC consolidator grant RESHAPE 311719 to H.G.]; Herculesstichting [AKUL/11/33 to H.G]; the Stichting tegen Kanker [2012-181 to H.G.]; and the National Institutes of Health [5R01 DK074398 and 5R01 DK091530 to K.E.M]. Deposited in PMC for release after 12 months.
Supplementary information available online at http://dev.biologists.org/lookup/doi/10.1242/dev.134767.supplemental
- Received January 4, 2016.
- Accepted August 8, 2016.