Epac1 inhibition ameliorates pathological angiogenesis through coordinated activation of Notch and suppression of VEGF signaling

Liu, Hua; Mei, Fang; Wang, Hui; Wong, Eitan; Cai, Jingjing; Toth, Emma; Luo, Pei; Li, Yue Ming; Zhang, Wenbo; Cheng, Xiaodong

doi:10.1126/sciadv.aay3566

Cited by 29 publications

(29 citation statements)

References 61 publications

(82 reference statements)

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“…Angiogenesis in general refers to the formation of new blood vessels from preexisting vasculature, a process that is vital for normal tissue growth, development, and wound healing ( Ren et al, 2019 ; Liu et al, 2020 ). Blood vessels make up complex vascular networks composed of arteries (arteriogenesis and de novo arteriogenesis), capillaries (vasculogenesis), and veins (venogenesis).…”

Section: Notch Signaling In Endothelial Cells and Angiogenesismentioning

confidence: 99%

Notch Signaling in Vascular Endothelial Cells, Angiogenesis, and Tumor Progression: An Update and Prospective

Akil

Gutiérrez-García

Guenter

et al. 2021

Front. Cell Dev. Biol.

114

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The Notch signaling pathway plays an essential role in a wide variety of biological processes including cell fate determination of vascular endothelial cells and the regulation of arterial differentiation and angiogenesis. The Notch pathway is also an essential regulator of tumor growth and survival by functioning as either an oncogene or a tumor suppressor in a context-dependent manner. Crosstalk between the Notch and other signaling pathways is also pivotal in tumor progression by promoting cancer cell growth, migration, invasion, metastasis, tumor angiogenesis, and the expansion of cancer stem cells (CSCs). In this review, we provide an overview and update of Notch signaling in endothelial cell fate determination and functioning, angiogenesis, and tumor progression, particularly in the development of CSCs and therapeutic resistance. We further summarize recent studies on how endothelial signaling crosstalk with the Notch pathway contributes to tumor angiogenesis and the development of CSCs, thereby providing insights into vascular biology within the tumor microenvironment and tumor progression.

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Section: Notch Signaling In Endothelial Cells and Angiogenesismentioning

confidence: 99%

Notch Signaling in Vascular Endothelial Cells, Angiogenesis, and Tumor Progression: An Update and Prospective

Akil

Gutiérrez-García

Guenter

et al. 2021

Front. Cell Dev. Biol.

114

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“…In addition, EPAC and its effector, Rap1, enhance cell–cell contacts, mediating the vascular endothelial barrier and decreasing cell permeability [ 110 , 111 ]. Regarding the impact of EPAC on VEC proliferation and migration, some studies reported an inhibitory effect, while others showed that EPAC increases VEC proliferation and migration, promoting angiogenesis [ 112 , 113 , 114 ]. The discrepancy in these studies could arise from differences in model used and vascular beds from which VECs were obtained.…”

Section: The Role Of Epac In Vsmcsmentioning

confidence: 99%

“…promoting angiogenesis [112][113][114]. The discrepancy in these studies could arise from differences in model used and vascular beds from which VECs were obtained.…”

Section: Phenotypic Switching: Vsmcs Proliferation and Migrationmentioning

confidence: 99%

EPAC in Vascular Smooth Muscle Cells

Wehbe

Nasser

Al-Dhaheri

et al. 2020

IJMS

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Vascular smooth muscle cells (VSMCs) are major components of blood vessels. They regulate physiological functions, such as vascular tone and blood flow. Under pathological conditions, VSMCs undergo a remodeling process known as phenotypic switching. During this process, VSMCs lose their contractility and acquire a synthetic phenotype, where they over-proliferate and migrate from the tunica media to the tunica interna, contributing to the occlusion of blood vessels. Since their discovery as effector proteins of cyclic adenosine 3′,5′-monophosphate (cAMP), exchange proteins activated by cAMP (EPACs) have been shown to play vital roles in a plethora of pathways in different cell systems. While extensive research to identify the role of EPAC in the vasculature has been conducted, much remains to be explored to resolve the reported discordance in EPAC’s effects. In this paper, we review the role of EPAC in VSMCs, namely its regulation of the vascular tone and phenotypic switching, with the likely involvement of reactive oxygen species (ROS) in the interplay between EPAC and its targets/effectors.

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“…For example, EPAC2 signaling is mainly involved in regulating intracellular calcium mobilization and vesicle trafficking associated with insulin secretion [18][19][20], synapse remodeling [21,22], learning, and social interactions [23][24][25]. EPAC1 signaling is known to crosstalk with signaling pathways such as PI3K/Akt [26,27], phospholipase C (PLC) [28][29][30], TGFβ/SMAD [31,32], leptin/STAT3 [33,34], VEGF and Notch [35][36][37], and contributes to the regulation of cardiovascular functions [38][39][40][41][42][43][44] and energy homeostasis [45]. In addition, dysregulations of EPAC1 signaling have been implicated in the development of numerous pathophysiological conditions in animals and humans, including cancer [46][47][48][49], chronic pain [50][51][52][53], infections [54,55], and vascular proliferative diseases [37,[56][57][58][59].…”

Section: Introductionmentioning

confidence: 99%

Origin and Isoform Specific Functions of Exchange Proteins Directly Activated by cAMP: A Phylogenetic Analysis

Cheng

2021

Cells

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Exchange proteins directly activated by cAMP (EPAC1 and EPAC2) are one of the several families of cellular effectors of the prototypical second messenger cAMP. To understand the origin and molecular evolution of EPAC proteins, we performed a comprehensive phylogenetic analysis of EPAC1 and EPAC2. Our study demonstrates that unlike its cousin PKA, EPAC proteins are only present in multicellular Metazoa. Within the EPAC family, EPAC1 is only associated with chordates, while EPAC2 spans the entire animal kingdom. Despite a much more contemporary origin, EPAC1 proteins show much more sequence diversity among species, suggesting that EPAC1 has undergone more selection and evolved faster than EPAC2. Phylogenetic analyses of the individual cAMP binding domain (CBD) and guanine nucleotide exchange (GEF) domain of EPACs, two most conserved regions between the two isoforms, further reveal that EPAC1 and EPAC2 are closely clustered together within both the larger cyclic nucleotide receptor and RAPGEF families. These results support the notion that EPAC1 and EPAC2 share a common ancestor resulting from a fusion between the CBD of PKA and the GEF from RAPGEF1. On the other hand, the two terminal extremities and the RAS-association (RA) domains show the most sequence diversity between the two isoforms. Sequence diversities within these regions contribute significantly to the isoform-specific functions of EPACs. Importantly, unique isoform-specific sequence motifs within the RA domain have been identified.

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Epac1 inhibition ameliorates pathological angiogenesis through coordinated activation of Notch and suppression of VEGF signaling

Abstract: Epac1 promotes pathological blood vessel formation and is a therapeutic target for vasoproliferative diseases.

Cited by 29 publications

References 61 publications

Notch Signaling in Vascular Endothelial Cells, Angiogenesis, and Tumor Progression: An Update and Prospective

Notch Signaling in Vascular Endothelial Cells, Angiogenesis, and Tumor Progression: An Update and Prospective

EPAC in Vascular Smooth Muscle Cells

Origin and Isoform Specific Functions of Exchange Proteins Directly Activated by cAMP: A Phylogenetic Analysis

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