A PKA/cdc42 Signaling Axis Restricts Angiogenic Sprouting by Regulating Podosome Rosette Biogenesis and Matrix Remodeling

Scientific Reports
Jodi L MacKeilDonald H Maurice

Abstract

Angiogenic sprouting can contribute adaptively, or mal-adaptively, to a myriad of conditions including ischemic heart disease and cancer. While the cellular and molecular systems that regulate tip versus stalk endothelial cell (EC) specification during angiogenesis are known, those systems that regulate their distinct actions remain poorly understood. Pre-clinical and clinical findings support sustained adrenergic signaling in promoting angiogenesis, but links between adrenergic signaling and angiogenesis are lacking; importantly, adrenergic agents alter the activation status of the cAMP signaling system. Here, we show that the cAMP effector, PKA, acts in a cell autonomous fashion to constitutively reduce the in vitro and ex vivo angiogenic sprouting capacity of ECs. At a cellular level, we observed that silencing or inhibiting PKA in human ECs increased their invasive capacity, their generation of podosome rosettes and, consequently, their ability to degrade a collagen matrix. While inhibition of either Src-family kinases or of cdc42 reduced these events in control ECs, only cdc42 inhibition, or silencing, significantly impacted them in PKA(Cα)-silenced ECs. Consistent with these findings, cell-based measurements of cdc42 acti...Continue Reading

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Citations

Feb 29, 2020·Current Opinion in Hematology·Florian AlonsoElisabeth Génot
Jan 26, 2021·Small GTPases·Paul RivierOlivier Destaing
Mar 23, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Wan-Jiao GaoHua Zhou

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Datasets Mentioned

BETA
GM6001

Methods Mentioned

BETA
GTPases
flow cytometry
biosensors
FRET
biosensor
transfection
fluorescence-activated cell sorting

Software Mentioned

GraphPad Prism
ImageJ
LAS X
Leica
FlowJo
Prism

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