Vascular Endothelial Growth Factor-A Exerts Diverse Cellular Effects via Small G Proteins, Rho and Rap

Shimizu, Akio; Zankov, Dimitar P.; Kurokawa-Seo, Misuzu; Ogita, Hisakazu

doi:10.3390/ijms19041203

Cited by 21 publications

(14 citation statements)

References 126 publications

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“…During the initial stages of angiogenesis, tip cells form filopodia and lamellipodia and orient them following the gradient of a vascular growth factor, typically VEGFA. The Ras homologue gene (Rho) and Ras-related protein (Rap) families of small G proteins are important mediators of VEGFA signaling in ECs (Shimizu et al, 2018). The Rho GTPases RhoA, Rac1, and Cdc42 interact with integrins at FAs where actin accumulates to initiate the formation of filopodia and lamellipodia (Lizama and Zovein, 2013).…”

Section: Ec Polarizationmentioning

confidence: 99%

A Computational Model of the Endothelial to Mesenchymal Transition

2020

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Endothelial cells (ECs) form the lining of lymph and blood vessels. Changes in tissue requirements or wounds may cause ECs to behave as tip or stalk cells. Alternatively, they may differentiate into mesenchymal cells (MCs). These processes are known as EC activation and endothelial-to-mesenchymal transition (EndMT), respectively. EndMT, Tip, and Stalk EC behaviors all require SNAI1, SNAI2, and Matrix metallopeptidase (MMP) function. However, only EndMT inhibits the expression of VE-cadherin, PECAM1, and VEGFR2, and also leads to EC detachment. Physiologically, EndMT is involved in heart valve development, while a defective EndMT regulation is involved in the physiopathology of cardiovascular malformations, congenital heart disease, systemic and organ fibrosis, pulmonary arterial hypertension, and atherosclerosis. Therefore, the control of EndMT has many promising potential applications in regenerative medicine. Despite the fact that many molecular components involved in EC activation and EndMT have been characterized, the system-level molecular mechanisms involved in this process have not been elucidated. Toward this end, hereby we present Boolean network model of the molecular involved in the regulation of EC activation and EndMT. The simulated dynamic behavior of our model reaches fixed and cyclic patterns of activation that correspond to the expected EC and MC cell types and behaviors, recovering most of the specific effects of simple gain and loss-of-function mutations as well as the conditions associated with the progression of several diseases. Therefore, our model constitutes a theoretical framework that can be used to generate hypotheses and guide experimental inquiry to comprehend the regulatory mechanisms behind EndMT. Our main findings include that both the extracellular microevironment and the pattern of molecular activity within the cell regulate EndMT. EndMT requires a lack of VEGFA and sufficient oxygen in the extracellular microenvironment as well as no FLI1 and GATA2 activity within the cell. Additionally Tip cells cannot undergo EndMT directly. Furthermore, the specific conditions that are sufficient to trigger EndMT depend on the specific pattern of molecular activation within the cell.

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Section: Ec Polarizationmentioning

confidence: 99%

A Computational Model of the Endothelial to Mesenchymal Transition

2020

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“…The angiogenic characteristics have been considered to be based on anosmin-1-induced promotion of endothelial cell migration, proliferation, and tube formation as shown in this study. Because angiogenic activities of endothelial cells are usually controlled by VEGFR-related signaling 20,33,34 , we focused on the association of anosmin-1 and VEGFR, and successfully identified the involvement of their direct binding in the activation of the receptor-dependent intracellular signaling. Although it has already been shown by another research group that anosmin-1 also directly binds to another growth factor receptor, FGFR1 24 , for the promotion of migration in neuroblast cells, this is the first study to reveal the interaction between anosmin-1 and VEGFR2 and novel functions of anosmin-1 in the angiogenic activity.…”

Section: Discussionmentioning

confidence: 99%

“…Blood vessels are reported to play an important role in maintaining OB because the radially migrating cells that constitute OB use blood vessels as a scaffold for their migration 18 . Although the VEGF-VEGFR axis plays an important role in vasculogenesis and angiogenesis, it might not be sufficient to generate mature vasculature for the appropriate development of tissues and organs [19][20][21] . Based on these findings, we hypothesized that, besides VEGF, anosmin-1 may associate with VEGF receptor for the enhancement of angiogenesis to develop OB.…”

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confidence: 99%

Anosmin-1 activates vascular endothelial growth factor receptor and its related signaling pathway for olfactory bulb angiogenesis

Matsushima

Shimizu

Kondo

et al. 2020

Sci Rep

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Anosmin-1 is a secreted glycoprotein encoded by the ANOS1 gene, and its loss of function causes Kallmann syndrome (KS), which is characterized by anosmia and hypogonadism due to olfactory bulb (OB) dysfunction. However, the physiological function of anosmin-1 remains to be elucidated. In KS, disordered angiogenesis is observed in OB, resulting in its hypoplasia. In this study, we examined the involvement of anosmin-1 in angiogenic processes. Anosmin-1 was detected on the vessel-like structure in OB of chick embryos, and promoted the outgrowth of vascular sprouts as shown by assays of OB tissue culture. Cell migration, proliferation, and tube formation of endothelial cells were induced by treatment with anosmin-1 as well as vascular endothelial growth factor-A (VEGF-A), and further enhanced by treatment with both of them. We newly identified that anosmin-1 activated VEGF receptor-2 (VEGFR2) by binding directly to it, and its downstream signaling molecules, phospholipase cγ1 (PLCγ1) and protein kinase C (PKC). These results suggest that anosmin-1 plays a key role in the angiogenesis of developing OB through the VEGFR2-PLCγ1-PKC axis by enhancing the VEGF function.

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“…VEGFs induce intracellular signal transduction upon binding to two types of transmembrane receptors: the VEGF receptors (VEGFRs), which are tyrosine kinase receptors (VEGF receptors 1, 2, and 3), or the neuropilins (NRPs) (NRP1 and NRP2) [40]. VEGFRs are type 1 transmembrane proteins that comprise seven extracellular immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic region [41].…”

Section: Vegfrs and Nrpsmentioning

confidence: 99%

The Role of Rho GTPases in VEGF Signaling in Cancer Cells

Baba

Farran

Khalil

et al. 2020

Analytical Cellular Pathology

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Vascular endothelial growth factors (VEGFs) consist of five molecules (VEGFA through D as well as placental growth factor) which are crucial for regulating key cellular and tissue functions. The role of VEGF and its intracellular signaling and downstream molecular pathways have been thoroughly studied. Activation of VEGF signal transduction can be initiated by the molecules’ binding to two classes of transmembrane receptors: (1) the VEGF tyrosine kinase receptors (VEGF receptors 1 through 3) and (2) the neuropilins (NRP1 and 2). The involvement of Rho GTPases in modulating VEGFA signaling in both cancer cells and endothelial cells has also been well established. Additionally, different isoforms of Rho GTPases, namely, RhoA, RhoC, and RhoG, have been shown to regulate VEGF expression as well as blood vessel formation. This review article will explore how Rho GTPases modulate VEGF signaling and the consequences of such interaction on cancer progression.

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Vascular Endothelial Growth Factor-A Exerts Diverse Cellular Effects via Small G Proteins, Rho and Rap

Cited by 21 publications

References 126 publications

A Computational Model of the Endothelial to Mesenchymal Transition

A Computational Model of the Endothelial to Mesenchymal Transition

Anosmin-1 activates vascular endothelial growth factor receptor and its related signaling pathway for olfactory bulb angiogenesis

The Role of Rho GTPases in VEGF Signaling in Cancer Cells

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