Ras Pathways on Prox1 and Lymphangiogenesis: Insights for Therapeutics

Bui, Khoa; Hong, Young‐Kwon

doi:10.3389/fcvm.2020.597374

Cited by 34 publications

(34 citation statements)

References 178 publications

(189 reference statements)

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“…Lymphangiogenesis is regulated by the VEGFC‐VEGFR3 axis and the ERK pathway. 31 In the present study, we found that Ang II‐induced hypertension inhibited lymphangiogenesis and down‐regulate the expression of lymphatic markers in mice hearts and decrease VEGFC in their serum, and SIRT3‐KO further suppressed these processes. In vitro, Ang II reduced function, expression of VEGFR3 and phosphorylation of ERK in LECs, which could be further down‐regulated by inhibition of SIRT3, but up‐regulated after SIRT3 overexpression, suggesting VEGFC‐VEGFR3 axis, and the ERK pathway may be associated with SIRT3‐regulated lymphangiogenesis.…”

Section: Discussionsupporting

confidence: 55%

Sirtuin 3 deficiency aggravates angiotensin II‐induced hypertensive cardiac injury by the impairment of lymphangiogenesis

Zhang¹,

Li²,

Suo³

et al. 2021

J Cellular Molecular Medi

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Lymphangiogenesis is possibly capable of attenuating hypertension‐induced cardiac injury. Sirtuin 3 (SIRT3) is an effective mitochondrial deacetylase that has the potential to modulate this process; however, its role in hypertension‐induced cardiac lymphangiogenesis to date has not been investigated. Our experiments were performed on 8‐week‐old wild‐type (WT), SIRT3 knockout (SIRT3‐KO) and SIRT3 overexpression (SIRT3‐LV) mice infused with angiotensin II (Ang II) (1000 ng/kg per minute) or saline for 28 days. After Ang II infusion, SIRT3‐KO mice developed a more severe cardiac remodelling, less lymphatic capillaries and lower expression of lymphatic marker when compared to wild‐type mice. In comparison, SIRT3‐LV restored lymphangiogenesis and attenuated cardiac injury. Furthermore, lymphatic endothelial cells (LECs) exposed to Ang II in vitro exhibited decreased migration and proliferation. Silencing SIRT3 induced functional decrease in LECs, while SIRT3 overexpression LECs facilitated. Moreover, SIRT3 may up‐regulate lymphangiogenesis by affecting vascular endothelial growth factor receptor 3 (VEGFR3) and ERK pathway. These findings suggest that SIRT3 could promote lymphangiogenesis and attenuate hypertensive cardiac injury.

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Section: Discussionsupporting

confidence: 55%

Sirtuin 3 deficiency aggravates angiotensin II‐induced hypertensive cardiac injury by the impairment of lymphangiogenesis

Zhang¹,

Li²,

Suo³

et al. 2021

J Cellular Molecular Medi

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“…While VEGF, a ligand of VEGFR2 is an essential factor for blood vessel development, VEGF-C is the major ligand that activates VEGFR3 for lymphatic vascular development ( 1 , 49 ). VEGF-C/VEGFR3 interaction activates PI3K-AKT and PKC-ERK pathways to regulate LECs proliferation, survival, and migration ( 50 ). It has been reported that VEGF-C treatment increased phospho-LATS1 and facilitated cytoplasmic YAP whereas VEGFR3 knockdown promoted nuclear localization of YAP, thereby suggesting that VEGF-C activates the Hippo signaling to repress YAP/TAZ in hLECs ( 45 ).…”

Section: Upstream Signals Regulating Hippo-yap/taz Pathway In Lecsmentioning

confidence: 99%

A novel role of Hippo-Yap/TAZ signaling pathway in lymphatic vascular development

Cha

Moon

Kim

2021

BMB Rep

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The lymphatic vasculature plays important role in regulating fluid homeostasis, intestinal lipid absorption, and immune surveillance in humans. Malfunction of lymphatic vasculature leads to several human diseases. Understanding the fundamental mechanism in lymphatic vascular development not only expand our knowledge, but also provide a new therapeutic insight. Recently, Hippo-YAP/TAZ signaling pathway, a key mechanism of organ size and tissue homeostasis, has emerged as a critical player that regulate lymphatic specification, sprouting, and maturation. In this review, we discuss the mechanistic regulation and pathophysiological significant of Hippo pathway in lymphatic vascular development. [

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“…Prox-1 is a major transcription factor of lymphatic development and mutations of the PROX1 gene have been reported in lymphedema patients ( Ricci et al, 2020 ). Studies on the effects of PROX1 knockout in mouse models induced lymphatic vasculature dysfunction ( Srinivasan and Oliver, 2011 ; Bui and Hong, 2020 ). Studies on the role of miRNAs in lymphedema-related inflammation are still lacking and some of the reported miRNAs have yet to be validated in human samples, using different diseases and models.…”

Section: Mirnas and Inflammation-induced Lymphangiogenesismentioning

confidence: 99%

Crosstalk Between microRNAs and the Pathological Features of Secondary Lymphedema

Yusof

Groen

Rosli

et al. 2021

Front. Cell Dev. Biol.

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Secondary lymphedema is characterized by lymphatic fluid retention and subsequent tissue swelling in one or both limbs that can lead to decreased quality of life. It often arises after loss, obstruction, or blockage of lymphatic vessels due to multifactorial modalities, such as lymphatic insults after surgery, immune system dysfunction, deposition of fat that compresses the lymphatic capillaries, fibrosis, and inflammation. Although secondary lymphedema is often associated with breast cancer, the condition can occur in patients with any type of cancer that requires lymphadenectomy such as gynecological, genitourinary, or head and neck cancers. MicroRNAs demonstrate pivotal roles in regulating gene expression in biological processes such as lymphangiogenesis, angiogenesis, modulation of the immune system, and oxidative stress. MicroRNA profiling has led to the discovery of the molecular mechanisms involved in the pathophysiology of auto-immune, inflammation-related, and metabolic diseases. Although the role of microRNAs in regulating secondary lymphedema is yet to be elucidated, the crosstalk between microRNAs and molecular factors involved in the pathological features of lymphedema, such as skin fibrosis, inflammation, immune dysregulation, and aberrant lipid metabolism have been demonstrated in several studies. MicroRNAs have the potential to serve as biomarkers for diseases and elucidation of their roles in lymphedema can provide a better understanding or new insights of the mechanisms underlying this debilitating condition.

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Ras Pathways on Prox1 and Lymphangiogenesis: Insights for Therapeutics

Cited by 34 publications

References 178 publications

Sirtuin 3 deficiency aggravates angiotensin II‐induced hypertensive cardiac injury by the impairment of lymphangiogenesis

Sirtuin 3 deficiency aggravates angiotensin II‐induced hypertensive cardiac injury by the impairment of lymphangiogenesis

A novel role of Hippo-Yap/TAZ signaling pathway in lymphatic vascular development

Crosstalk Between microRNAs and the Pathological Features of Secondary Lymphedema

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