EMT / EMT_REGULATORS
EMT / CYTOSKELETON_POLARITY
EMT / CELL_CELL_ADHESIONS
EMT / CELL_MATRIX_ADHESIONS
EMT / ECM
EMT / TIGHT_JUNCTIONS
EMT / GAP_JUNCTIONS
EMT / ADHERENS_JUNCTIONS
EMT / DESMOSOMES
Angiogenesis is the formation of vessels from the existing vascular structure
Angiogenesis is a crucial biological response in wound healing, menstrual cycle, tumor aggression, and diabetic retinopathy.
Endothelial sprouting, which requires extracellular matrix remodeling and endothelial cell migration, is the prerequisite process of angiogenic response.
Such biological response relies on highly coordinated gene expression in a temporal and spatial manner.
Increasing evidence revealed that miRs play a pivotal role in the angiogenic process.
miR200b, one member of miR200, is hypoxia-inducible and down-regulates ETS1 transcription factor, subsequently promoting angiogenesis in HMECs.
HMECs are Human Microvascular Endothelial Cells
Angiogenesis depends on the adhesive interactions of vascular cells.
The adhesion receptor integrin aVb3 was identified as a marker of angiogenic vascular tissue.
Integrin aVb3 was expressed on blood vessels in human wound granulation tissue but not in normal skill.
Integrin aVb3 provides a specific trasmembrane signal that potentiates the survival of angiogenic vascular cells in vivo.
Angiogenesis is the development of new blood vessels from existing ones.
Angiogenesis is central to a variety of physiologic phenomena, including tissue growth and repair, fetal development, and the female reproductive cycle
Angiogenesis is crucial for supplying oxygen and nutrients to specific pathologic tissues such as neoplasms.
Angiogenic signals can be matrix attached or freely diffusible
Endothelial cells (ECs) are activated by angiogenic factors such as VEGFs or FGF2 upon which they release matrix metalloproteinases that degrade the extracellular matrix in the immediate surrounding.
ECs are now free to migrate.
ECs align and form tubes that anastomose and to which parenchymal cells are recruited to form stable new blood vessels.
Later angiogenic ECs return to quiescence
e_re369( EMT ):
Ets-1 is a key transcription factor that is known to support angiogenesis.
Certain pro-angiogenic stimulus induce Ets-1 expression, such as:
VEGF increased the level of ETS1 mRNA in human umbifical vein endothelial cells and lung microvascular endothelial cells over 5-fold.
Protein levels were shown to increase concordantly.
VEGF is a predominant angiogenic factor that mediates ocular neovascularization.
VEGF is increased by hypoxia, which is one of the primary stimuli for ocular neovascularization.
VEGF induces Ets-1 expression in bovine retinal endothelial cells and its expression is PKC/ERK pathway-dependent.
Ets-1 up-regulation is involved in the development of retinal neovascularization, and inhibition of Ets-1 may be beneficial in the treatment of ischemic ocular diseases
Angiotensin II is a potent mediator of vascular inflammation through the generation of reactive oxygen species (ROS).
Ang II–induced ROS production and medial hypertrophy in the thoracic aorta were markedly diminished as a result of blocking Ets-1.
Ets-1 functions as a critical downstream transcriptional mediator of Ang II ROS generation by regulating the expression of NAD(P)H oxidase subunits such as p47phox
Angiotensin II increases the expression of the transcription factor ETS-1 in mesangial cells
Mesangial cells are specialized cells around blood vessels in the kidneys, at the mesangium
Fibroblast growth factor FGF1, a prototypic member of the FGF family, has the ability to stimulate angiogenesis in an in vivo model of angiogenesis.
This FGF1-mediated angiogenesis involves in the PI3K/AKT pathway.
Both activity and mRNA expression levels of the Ets1 molecule were increased in response to FGF1 overexpression
Ets-1 activation is a requisite for FGF1-mediated angiogenesis in vivo.
e_re375( EMT ):
TCF8 (ZEB1) is a negative regulator of angiogenesis in vitro, ex vivo, and in vivo.
e_re422( EMT ):
The soluble form of the cancer-associated L1 cell adhesion molecule is a pro-angiogenic factor.
Soluble L1CAM was able to stimulate growth and invasion of bovine aortic endothelial cells to a similar extent as the VEGF-A (isoform 165 amino acids)
Stimulation with soluble L1CAM led to tube formation of bovine aortic endothelial cells in vitro and increased angiogenesis in vivo.
The pro- angiogenic effect of soluble L1CAM could be abolished by treatment with the L1CAM specific antibody chCE7.
PDAC Endothelial cells are characterized by elevated L1CAM expression compared to HUVEC cells where L1CAM expression can be induced by TNFaIFNgor TGFB1
Antibody-mediated blockade of L1CAM abolished tube formation and tumor endothelial cell transmigration.
Integrins, especiallyv3, play a role in the activation ofVEGFR-
2, a key player in angiogenesis. Because both sL1 and VEGF are present in ascites fluid of ovarian carcinoma patients (Fogel et al., 2003a;Zebrowskiet al.,1999),weanalyzedtheactivation ofVEGFR-
2 in BAE cells in the presence of sL1 and VEGF-A165 (Fig. 6). The three-fold higher stimulation of VEGFR-2 with the combination of bothcomponents incomparison tothe single treatmentwithVEGF-
A165 could be explained by the activation of v3 integrin through the RGD sequence in the L1 molecule. v3 integrin is involved in the full activation of VEGFR-2 triggered by VEGF-A165 (Soldi et al., 1999). These findings are consistent with results published by Hall and co-workers (2004); Hall and Hubbell (2004). They showed that ligation of mouse L1Ig6 to v3 integrin stimulates VEGFR-2 and induces angiogenesis in vivo
Overall, these data point to a role of L1CAM as a pro-angiogenic factor and the potential of an anti-L1CAM antibody therapy in interfering with tumor angiogenesis (see below).
e_re423( EMT ):
Interaction between integrin avb3 and extracellular matrix is crucial for endothelial cells sprouting from capillaries and for angiogenesis.
Tyrosine-phosphorylated VEGFR2 co-immunoprecipitated with b3 integrin subunit, but not with b1 or b5, from cells stimulated with VEGFA (165 amino acid isoform)
VEGFR2 phosphorylation and mitogenicity induced by VEGFA were enhanced in cells plated on the avb3 ligand, vitronectin, compared with cells plated on the a5b1 ligand, fibronectin or the a2b1 ligand, collagen.
A new role for avb3 integrin in the activation of an in vitro angiogenic program in endothelial cells:
Besides being the most important survival system for nascent vessels by regulating cell adhesion to matrix, avb3 integrin participates in the full activation of VEGFR2 triggered by VEGFA.
e_re1195( EMT ):
TWIST1 associates with enhanced tumor microvessel vasculature (angiogenesis)
TWIST1 associates with VEGF expression in hepatocarcinomas
e_re1239( EMT ):
Differential roles for Snail and E47 (both are E-cadherin repressors) in tumour progression:
Snail is implicated in promoting the initial invasion
E47 plays an active role in tumour cell growth by promoting angiogenesis.
e_re1240( EMT ):
Angiognesis is triggered by hypoxia and inflammation, conditions that are also known inducers of EMT
e_re1241( EMT ):
HIF-1 plays critical roles in angiogenesis during embryonic development and disease pathogenesis
e_re1251( EMT ):
ID is so-called Inhibitor of differentiation/DNA binding proteins
ID proteins is frequently deregulated in advanced human malignancies.
ID proteins can participate in blocking differentiation, increasing proliferation, tissue invasiveness, and angiogenesis.
e_re4( EMT ):
TCF8 (ZEB1) is up-regulated in endothelial cells during angiogenesis, acting as a negative regulator.
In NMuMG cells treated with TGFB1 Snail1 RNA and protein are induced 1 h after addition of the cytokine preceding Zeb1 up-regulation that requires 6–8 h.
Zeb1 gene expression is caused by increased RNA levels but also by enhanced protein stability and is markedly dependent on Snail1 because depletion of this protein prevents Zeb1 protein and RNA up-regulation
Snail1 controls Zeb1 expression at multiple levels and acts cooperatively with Twist in the ZEB1 gene transcription induction
HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression.
HMGA2 cooperates with SMAD3 and SMAD4 to execute a dramatic super-induction of the SNAIL1 promoter.
Same results were obtained with SNAI2, ZEB1, ZEB2 and TWIST1
HMGA2 cooperates with TGFB1 signaling to represse ID2 transcriptomal expression
In compartment: Nucleus
Participates in complexes:
Participates in reactions:
As Reactant or Product:
- TWIST1|S68_pho@Nucleus → Angiogenesis@Nucleus
- TCF3@Nucleus → Angiogenesis@Nucleus
- Hypoxia@Cytoplasm → Angiogenesis@Nucleus
- HIF_alpha_*@Cytoplasm → Angiogenesis@Nucleus
- HIF1B*@Cytoplasm → Angiogenesis@Nucleus
- ID*@Nucleus → Angiogenesis@Nucleus
- ETS1@Nucleus → Angiogenesis@Nucleus
- ZEB1@Nucleus → Angiogenesis@Nucleus
- VEGFA@Extracellular space → Angiogenesis@Nucleus
- L1CAM@Cytoplasm → Angiogenesis@Nucleus
- ITGAV:ITGB3@Cytoplasm → Angiogenesis@Nucleus
- rCTGF@Nucleus → Angiogenesis@Nucleus
- rTSP1*@Nucleus → Angiogenesis@Nucleus
- APC2*:CK1_epsilon_*:CTHRC1:DAAM1:DVL*|pho|pho|pho:GSK3*:ROR2|S864_pho|pho|pho:RSPO3:SYN4*:VANGL*|pho|pho|pho|pho:WGEF*:_beta_-Arrestin2*@Cytoplasm → Angiogenesis@Nucleus