VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells

Jerafi-Vider, Ayelet; Bassi, Ivan; Moshe, Noga; Tevet, Yaara; Hen, Gideon; Splittstoesser, Daniel; Shin, Masahiro; Lawson, Nathan D.; Yaniv, Karina

doi:10.1016/j.celrep.2021.109255

Cited by 38 publications

(23 citation statements)

References 72 publications

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“…During zebrafish development, Vegfc acts in both an autocrine and paracrine manner to induce venous as well as lymphatic sprouting by inducing cell cycle arrest via Vegfr3. 32,66 Similarly, our data showing emilin2a expression by cECs and EPDCs during cardiac regeneration suggest that Vegfc acts in both an autocrine and paracrine manner to promote emilin2a expression. Importantly, we found that global overexpression of emilin2a stimulates coronary revascularization and reduces scarring after cardiac injury.…”

Section: Discussionmentioning

confidence: 55%

A Vegfc-Emilin2a-Cxcl8a Signaling Axis Required for Zebrafish Cardiac Regeneration

El-Sammak

Yang

Guenther

et al. 2022

Circulation Research

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Background: Ischemic heart disease following the obstruction of coronary vessels leads to the death of cardiac tissue and the formation of a fibrotic scar. In contrast to adult mammals, zebrafish can regenerate their heart after injury, enabling the study of the underlying mechanisms. One of the earliest responses following cardiac injury in adult zebrafish is coronary revascularization. Defects in this process lead to impaired cardiomyocyte repopulation and scarring. Hence, identifying and investigating factors that promote coronary revascularization holds great therapeutic potential. Methods: We used whole mount imaging, immunohistochemistry and histology to assess various aspects of zebrafish cardiac regeneration. Deep transcriptomic analysis allowed us to identify targets and potential effectors of Vegfc (vascular endothelial growth factor C) signaling. We used newly generated loss- and gain-of-function genetic tools to investigate the role of Emilin2a and Cxcl8a-Cxcr1 signaling in cardiac regeneration. Results: We first show that regenerating coronary endothelial cells upregulate vegfc upon cardiac injury in adult zebrafish and that Vegfc signaling is required for their proliferation during regeneration. Notably, blocking Vegfc signaling also significantly reduces cardiomyocyte dedifferentiation and proliferation. Using transcriptomic analyses, we identified emilin2a as an effector of Vegfc signaling and found that manipulation of emilin2a expression can modulate coronary revascularization as well as cardiomyocyte proliferation. Mechanistically, Emilin2a induces the expression of the chemokine gene cxcl8a in epicardium-derived cells, while cxcr1 , the Cxcl8a receptor gene, is expressed in coronary endothelial cells. We further show that Cxcl8a-Cxcr1 signaling is also required for coronary endothelial cell proliferation during cardiac regeneration. Conclusions: These data show that after cardiac injury, coronary endothelial cells upregulate vegfc to promote coronary network reestablishment and cardiac regeneration. Mechanistically, Vegfc signaling upregulates epicardial emilin2a and cxcl8a expression to promote cardiac regeneration. These studies aid in understanding the mechanisms underlying coronary revascularization in zebrafish, with potential therapeutic implications to enhance revascularization and regeneration in injured human hearts.

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Section: Discussionmentioning

confidence: 55%

A Vegfc-Emilin2a-Cxcl8a Signaling Axis Required for Zebrafish Cardiac Regeneration

El-Sammak

Yang

Guenther

et al. 2022

Circulation Research

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“…VEGFC has long been considered to be the main regulator of lymphangiogenesis ( 72 ). However, multiple studies indicate that it also plays an important role in regulating endothelial sprouting ( 73 – 75 ). These data raise the possibility that treatment with the anti-VEGFA antibody, bevacizumab, may not be sufficient to inhibit angiogenesis in pituitary tumors.…”

Section: Discussionmentioning

confidence: 99%

Sprouting Angiogenesis in Human Pituitary Adenomas

Zhou

Zhu

et al. 2022

Front. Oncol.

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IntroductionAngiogenesis in pituitary tumors is not fully understood, and a better understanding could help inform new pharmacologic therapies, particularly for aggressive pituitary tumors.Materials and Methods219 human pituitary tumors and 12 normal pituitary glands were studied. Angiogenic genes were quantified by an angiogenesis qPCR array and a TaqMan probe-based absolute qPCR. Angiogenesis inhibition in pituitary tumors was evaluated in vitro with the endothelial tube formation assay and in vivo in RbΔ19 mice.Results71 angiogenic genes, 40 of which are known to be involved in sprouting angiogenesis, were differentially expressed in pituitary tumors. Expression of endothelial markers CD31, CD34, and ENG was significantly higher in pituitary tumors, by 5.6, 22.3, and 8.2-fold, respectively, compared to in normal pituitary tissue. There was no significant difference in levels of the lymphatic endothelial marker LYVE1 in pituitary tumors compared with normal pituitary gland tissue. Pituitary tumors also expressed significantly higher levels of angiogenesis growth factors, including VEGFA (4.2-fold), VEGFB (2.2), VEGFC (19.3), PGF (13.4), ANGPT2 (9.2), PDGFA (2.7), PDGFB (10.5) and TGFB1 (3.8) compared to normal pituitary tissue. Expression of VEGFC and PGF was highly correlated with the expression of endothelial markers in tumor samples, including CD31, CD34, and ENG (endoglin, a co-receptor for TGFβ). Furthermore, VEGFR inhibitors inhibited angiogenesis induced by human pituitary tumors and prolonged survival of RbΔ19 mice.ConclusionHuman pituitary tumors are characterized by more active angiogenesis than normal pituitary gland tissue in a manner consistent with sprouting angiogenesis. Angiogenesis in pituitary tumors is regulated mainly by PGF and VEGFC, not VEGFA and VEGFB. Angiogenesis inhibitors, such as the VEGFR2 inhibitor cabozantinib, may merit further investigation as therapies for aggressive human pituitary tumors.

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“…Apart from reduction of eNOS, DNA damage, mitochondrial dysfunction, oxidative stress, telomere dysfunction and other stressors induce several tumor suppressor genes including p53 and lead to cellular senescence, the permanent state of cell arrest. ( Jerafi-Vider et al, 2021 ; Sun and Feinberg, 2021 ). Cellular senescence is originally a physiological protective mechanism to prevent the development of tumor, however, when such senescent cells accumulate in number it leads to aging of cells ( López-Otín et al, 2013 ).…”

Section: P53 and Endothelial Dysfunctionmentioning

confidence: 99%

The role of p53 in the alternation of vascular functions

Chan

Kwok

et al. 2022

Front. Pharmacol.

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Ageing is a risk factor for many degenerative diseases. Cardiovascular diseases (CVDs) are usually big burdens for elderly, caregivers and the health system. During the aging process, normal functions of vascular cells and tissue progressively lost and eventually develop vascular diseases. Endothelial dysfunction, reduced bioavailability of endothelium-derived nitric oxide are usual phenomena observed in patients with cardiovascular diseases. Myriad of studies have been done to investigate to delay the vascular dysfunction or improve the vascular function to prolong the aging process. Tumor suppressor gene p53, also a transcription factor, act as a gatekeeper to regulate a number of genes to maintain normal cell function including but not limited to cell proliferation, cell apoptosis. p53 also crosstalk with other key transcription factors like hypoxia-inducible factor 1 alpha that contribute to the progression of cardiovascular diseases. Therefore, in recent three decades, p53 has drawn scientists’ attention on its effects in vascular function. Though the role of tumor suppressor gene p53 is still not clear in vascular function, it is found to play regulatory roles and may involve in vascular remodeling, atherosclerosis or pulmonary hypertension. p53 may have a divergent role in endothelial and vascular muscle cells in those conditions. In this review, we describe the different effects of p53 in cardiovascular physiology. Further studies on the effects of endothelial cell-specific p53 deficiency on atherosclerotic plaque formation in common animal models are required before the therapeutic potential can be realized.

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VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells

Abstract: Highlights d Endothelial cells sprout from the PCV in G1 phase of the cell cycle d VEGFC/FLT4/ERK induce p53-, p21-, and p27-mediated cellcycle arrest to enable sprouting d Forced G1 cell-cycle arrest results in ectopic sprouting of undifferentiated ECs

Cited by 38 publications

References 72 publications

A Vegfc-Emilin2a-Cxcl8a Signaling Axis Required for Zebrafish Cardiac Regeneration

A Vegfc-Emilin2a-Cxcl8a Signaling Axis Required for Zebrafish Cardiac Regeneration

Sprouting Angiogenesis in Human Pituitary Adenomas

The role of p53 in the alternation of vascular functions

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