Endothelial cell cycle state determines propensity for arterial-venous fate

Chavkin, Nicholas W.; Genet, Gaël; Poulet, Mathilde; Jeffery, Erin; Marziano, Corina; Genet, Nafiisha; Vasavada, Hema; Nelson, Elizabeth A.; Acharya, Bipul R.; Kour, Anupreet; Aragon, Jordon; McDonnell, Stephanie P.; Huba, Mahalia; Sheynkman, Gloria; Walsh, Kenneth; Hirschi, Karen K.

doi:10.1038/s41467-022-33324-7

Cited by 42 publications

(41 citation statements)

References 80 publications

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“…S9 C and D). Recent work suggests that arterial ECs under high FSS are in late G1 arrest (31), suggesting activation of CDK4 or CDK2. Flavopiripol targets these isoforms, though it also inhibits CDK9 (32).…”

Section: Resultsmentioning

confidence: 99%

“…These findings suggest a connection between artery remodeling and the cell cycle. Recent work has shown that arterial specification, which is associated with high FSS, requires cell cycle arrest, specifically in late G1 (31). Physiological FSS is well known to induce cell cycle arrest, though the specific phase has not been explored (reviewed in ref.…”

Section: Discussionmentioning

confidence: 99%

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Activation of Smad2/3 signaling by low fluid shear stress mediates artery inward remodeling

Deng¹,

Min

Baeyens

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Endothelial cell (EC) sensing of wall fluid shear stress (FSS) from blood flow governs vessel remodeling to maintain FSS at a specific magnitude or set point in healthy vessels. Low FSS triggers inward remodeling to restore normal FSS but the regulatory mechanisms are unknown. In this paper, we describe the signaling network that governs inward artery remodeling. FSS induces Smad2/3 phosphorylation through the type I transforming growth factor (TGF)-β family receptor Alk5 and the transmembrane protein Neuropilin-1, which together increase sensitivity to circulating bone morphogenetic protein (BMP)-9. Smad2/3 nuclear translocation and target gene expression but not phosphorylation are maximal at low FSS and suppressed at physiological high shear. Reducing flow by carotid ligation in rodents increases Smad2/3 nuclear localization, while the resultant inward remodeling is blocked by the EC-specific deletion of Alk5. The flow-activated MEKK3/Klf2 pathway mediates the suppression of Smad2/3 nuclear translocation at high FSS, mainly through the cyclin-dependent kinase (CDK)-2-dependent phosphosphorylation of the Smad linker region. Thus, low FSS activates Smad2/3, while higher FSS blocks nuclear translocation to induce inward artery remodeling, specifically at low FSS. These results are likely relevant to inward remodeling in atherosclerotic vessels, in which Smad2/3 is activated through TGF-β signaling.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Activation of Smad2/3 signaling by low fluid shear stress mediates artery inward remodeling

Deng¹,

Min

Baeyens

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…Cell proliferation and migration are integral to angiogenesis. 58,59 Proangiogenic stimuli, like VEGF and hypoxia, increased FAM222A mRNA and protein levels while silencing FAM222A decreased VEGF-induced EC migration, proliferation, vascular spouting in vitro, ex vivo, and in Matrigel plug revascularization in vivo (Figure 1H and 1N, 2A through 2G); FAM222A overexpression had opposite effects. FAM222A silencing did not alter activation of p53 or p53-mediated p21 (data not shown) nor induce apoptosis, excluding these as explanations for decreased cell proliferation and migration after FAM222A silencing.…”

Section: Discussionmentioning

confidence: 98%

FAM222A, Part of the BET-Regulated Basal Endothelial Transcriptome, Is a Novel Determinant of Endothelial Biology and Angiogenesis—Brief Report

Tzani,

Haemmig,

Cheng

et al. 2024

ATVB

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Background: BETs (bromodomain and extraterminal domain–containing epigenetic reader proteins), including BRD4, orchestrate transcriptional programs induced by pathogenic stimuli, as intensively studied in cardiovascular disease and elsewhere. In endothelial cells (ECs), BRD4 directs induced proinflammatory, proatherosclerotic transcriptional responses; BET inhibitors, like JQ1, repress these effects and decrease atherosclerosis. While BET effects in pathogenic conditions have prompted therapeutic BET inhibitor development, BET action under basal conditions, including ECs, has remained understudied. To understand BET action in basal endothelial transcriptional programs, we first analyzed EC RNA-Seq data in the absence versus presence of JQ1 before using BET regulation to identify novel determinants of EC biology and function. Methods: RNA-Seq datasets of human umbilical vein ECs without and with JQ1 treatment were analyzed. After identifying C12orf34, also known as FAM222A (family with sequence similarity 222 member A), as a previously unreported, basally expressed, potently JQ1-induced EC gene, FAM222A was studied in endothelial and angiogenic responses in vitro using small-interference RNA silencing and lentiviral overexpression, in vitro, ex vivo and in vivo, including aortic sprouting, matrigel plug assays, and murine neonatal oxygen-induced retinopathy. Results: Resting EC RNA-Seq data indicate BETs direct transcriptional programs underlying core endothelial properties including migration, proliferation, and angiogenesis. BET inhibition in resting ECs also significantly induced a subset of mRNAs, including FAM222A—a unique BRD4-regulated gene with no reported EC role. Silencing endothelial FAM222A significantly decreased cellular proliferation, migration, network formation, aorta sprouting, and Matrigel plug vascularization through coordinated modulation of VEGF (vascular endothelial growth factor) and NOTCH mediator expression in vitro, ex vivo, or in vivo; lentiviral FAM222A overexpression had opposite effects. In vivo, siFAM222A significantly repressed retinal revascularization in neonatal murine oxygen-induced retinopathy through similar angiogenic signaling modulation. Conclusions: BET control over the basal endothelial transcriptome includes FAM222A, a novel, BRD4-regulated, key determinant of endothelial biology and angiogenesis.

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“…In these vascular beds, Dll4-Notch signaling interactions at the sprouting front induces an endothelial fate switch and specifies future arterial cells among the tip cell progeny (Fang et al, 2017; Hasan et al, 2017; Hou et al, 2022; Pitulescu et al, 2017; Xu et al, 2014). More recent evidence points to a priming mechanism of tip cells towards an arterial fate that is linked to the Notch pathway directly inducing metabolic and cell cycle arrest (Chavkin et al, 2022; Fang et al, 2017; Luo et al, 2021; Su et al, 2018) and subsequently more responsiveness to migratory cues (Hasan et al, 2017; Luo et al, 2021; Pitulescu et al, 2017). The Cxcl12-Cxcr4 chemokine signaling axis has been identified as a critical downstream target of Notch in this process (Hasan et al, 2017; Luo et al, 2021; Pitulescu et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Coronary vessel assembly involves patterned endocardial sprouting and tip-cell-to artery specification

Cano

Paech

Kanda

et al. 2022

Preprint

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The coronary vasculature comprises superficial coronary veins and deeper coronary arteries and capillaries that critically support the high metabolic activity of the beating heart. Understanding how different endothelial progenitor sources jointly shape and remodel the coronary vasculature into its adult pattern has recently attracted great research interest, and spurred much debate. Here, using lineage tracing tools in combination with three-dimensional imaging, live-imaging in explants and single-cell transcriptional profiling, we demonstrate that sprouting angiogenesis drives both sinus venosus and endocardial contribution to coronary plexus. Whereas previous studies limit endocardial contribution to coronary vessels to the interventricular septum and ventral aspect of the heart, our study demonstrates extensive endocardial sprouting angiogenesis in the free ventricular walls. In particular, we identify a distinct subpopulation of endocardial cells that express future coronary markers and reside in both the embryonic and adult ventricular wall endocardium. Most importantly, we provide evidence for sprouting angiogenesis from both endocardium and subepicardial plexus towards the inner myocardial wall to determine pre-arterial specification. Additionally, sprouting from the endocardium leads to the establishment of perfused connections to the advancing coronary plexus, also followed by transitioning to the pre-arterial cell state. Distinct molecular profiles characterize sprouting populations in the intramyocardial and subepicardial layers that shape the prospective coronary arteries and veins, respectively. Harnessing the endocardial progenitors and targeting the distinct sprouting populations may in the future serve to tailor cardiac vascular adaptations for therapeutic purposes.

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Endothelial cell cycle state determines propensity for arterial-venous fate

Cited by 42 publications

References 80 publications

Activation of Smad2/3 signaling by low fluid shear stress mediates artery inward remodeling

Activation of Smad2/3 signaling by low fluid shear stress mediates artery inward remodeling

FAM222A, Part of the BET-Regulated Basal Endothelial Transcriptome, Is a Novel Determinant of Endothelial Biology and Angiogenesis—Brief Report

Coronary vessel assembly involves patterned endocardial sprouting and tip-cell-to artery specification

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