cAMP-dependent protein kinase A (PKA) regulates angiogenesis by modulating tip cell behavior in a Notch-independent manner

Nedvetsky, Pavel I.; Zhao, Xuyao; Mathivet, Thomas; Aspalter, Irene M.; Stanchi, Fabio; Metzger, Ross J.; Mostov, Keith E.; Gerhardt, Holger

doi:10.1242/dev.134767

Cited by 27 publications

(33 citation statements)

References 61 publications

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“…Thus, PKA(C)-KD HAECs are not imparted with a competitive advantage during angiogenesis by upregulating genes associated with tip cell sprouting. Interestingly, these findings are consistent with previous work 36 in which endothelial-specific expression of a dominant-negative PKA caused vascular hyper-sprouting in the mouse retina, independently of Notch-signaling.…”

Section: Resultssupporting

confidence: 92%

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

MacKeil

Brzezińska

Burke-Kleinman

et al. 2019

Sci Rep

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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 activity revealed that PKA activation inhibits EC cdc42 activity, at least in part, by promoting its interaction with the inhibitory regulator, guanine nucleotide dissociation inhibitor-α (RhoGDIα).

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Section: Resultssupporting

confidence: 92%

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

MacKeil

Brzezińska

Burke-Kleinman

et al. 2019

Sci Rep

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“…Increasing cAMP by blockade of PDE5 with sildenafil rescues mitochondrial stress by increasing the expression of PRC via direct binding of CREB to the PRC promoter, increasing mitochondrial biogenesis leading to increased angiogenesis. cAMP has beenshown to be a key driver of angiogenesis downstream of VEGF signaling(26) Our findings show that sildenafil, although known as a PDE5 inhibitor, decreasing the turnover of cGMP, also results in an increase in cAMP.Others have also shown that sildenafil treatment can increase cAMP in EC and other cell types(27- 29…”

supporting

confidence: 61%

PDE5 inhibition rescues mitochondrial dysfunction and angiogenic responses induced by Akt3 inhibition by promotion of PRC expression

Corum

Jenkins

Heslop

et al. 2020

Journal of Biological Chemistry

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Akt3 regulates mitochondrial content in endothelial cells through the inhibition of PGC-1α nuclear localization and is also required for angiogenesis. However, whether there is a direct link between mitochondrial function and angiogenesis is unknown. Here we show that Akt3 depletion in primary endothelial cells (EC) results in decreased uncoupled oxygen consumption, increased fission, decreased membrane potential and increased expression of the mitochondria-specific protein chaperones, HSP60 and HSP10, suggesting that Akt3 is required for mitochondrial homeostasis. Direct inhibition of mitochondrial homeostasis by the model oxidant paraquat results in decreased angiogenesis showing a direct link between angiogenesis and mitochondrial function. Next, in exploring functional links to PGC-1α, the master regulator of mitochondrial biogenesis, we searched for compounds that induce this process. We found that sildenafil, a phosphodiesterase 5 (PDE5) inhibitor induced mitochondrial biogenesis as measured by increased uncoupled oxygen consumption, mitochondrial DNA content and voltage-dependent anion channel protein expression. Sildenafil rescued the effects on mitochondria by Akt3 depletion or pharmacological inhibition and promoted angiogenesis, further supporting that mitochondrial homeostasis is required for angiogenesis. Sildenafil also induces the expression of PGC-1 family member, PRC and can compensate for PGC-1α activity during mitochondrial stress by an Akt3-independent mechanism. The induction of PRC by sildenafil is dependent upon cAMP and the transcription factor CREB. Thus, PRC can functionally substitute during Akt3 depletion for absent PGC-1α activity to restore mitochondrial homeostasis and promote angiogenesis. These findings show that mitochondrial homeostasis as controlled by the PGC family of transcriptional activators is required for angiogenic responses.

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“…CAMP-dependent protein kinase A (PKA) is signaling hub during angiogenesis, which regulates tip/stalk cell behavior by (Lin et al 2016) WSP-1 osteosarcoma VEGF-A expression -Inhibiting miR-381 and FAK/JNK/HIF-1alpha signaling pathways (Tsai et al 2017) WSP-2 endothelial cells Antiangiogenesis -Matrix metalloproteinase 14 (MMP14) (Butler et al 2017) WSP-3 Chondrosarcoma VEGF-A expression and angiogenesis -Inhibiting miR-452 via the c-Src and p38 pathways (Lin et al 2017) restraining tip cells formation. In zebrafish, the ability of PKA to regulate the tip cells is not related to notch signaling (Nedvetsky et al 2016).…”

Section: Intracellular Networkmentioning

confidence: 99%

The endothelial tip-stalk cell selection and shuffling during angiogenesis

Chen

Xia

Wang

et al. 2019

J. Cell Commun. Signal.

107

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Angiogenesis is a critical, fine-tuned, multi-staged biological process. Tip-stalk cell selection and shuffling are the building blocks of sprouting angiogenesis. Accumulated evidences show that tip-stalk cell selection and shuffling are regulated by a variety of physical, chemical and biological factors, especially the interaction among multiple genes, their products and environments. The classic Notch-VEGFR, Slit-Robo, ECM-binding integrin, semaphorin and CCN family play important roles in tipstalk cell selection and shuffling. In this review, we outline the progress and prospect in the mechanism and the roles of the various molecules and related signaling pathways in endothelial tip-stalk cell selection and shuffling. In the future, the regulators of tip-stalk cell selection and shuffling would be the potential markers and targets for angiogenesis. Keywords Angiogenesis. Endothelial cells. Tip-stalk cell selection. Tip-stalk shuffling. Signaling pathway Endothelial cells (ECs) remain quiescent in most healthy adults. Angiogenesis, the growth of new blood vessels occurs under many physiological conditions, such as embryo development, and pathological conditions, such as chronic inflammation, certain immune reactions and cancers (Potente et al. 2011). The growth of vascular system involves tip cell selection, sprout formation, tip cell migration, stalk cell proliferation, and ultimately vascular stabilization. The distal end of each sprout contains a specialized EC, termed tip cell. Tip cells are motile, invasive and highly polarized with a large * Xiaoling Zhang

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cAMP-dependent protein kinase A (PKA) regulates angiogenesis by modulating tip cell behavior in a Notch-independent manner

Cited by 27 publications

References 61 publications

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

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

PDE5 inhibition rescues mitochondrial dysfunction and angiogenic responses induced by Akt3 inhibition by promotion of PRC expression

The endothelial tip-stalk cell selection and shuffling during angiogenesis

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