scholarly journals Zebrafish G protein γ2 is required for VEGF signaling during angiogenesis

Blood ◽  
2006 ◽  
Vol 108 (1) ◽  
pp. 160-166 ◽  
Author(s):  
TinChung Leung ◽  
Hui Chen ◽  
Anna M. Stauffer ◽  
Kathryn E. Giger ◽  
Soniya Sinha ◽  
...  
Keyword(s):  
Blood Vessels ◽  
G Protein ◽  
Tyrosine Kinases ◽  
Vascular Endothelial ◽  
Breast Cancers ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Vegf Signaling ◽  
Promising Treatment ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is a major mediator of pathologic angiogenesis, a process necessary for the formation of new blood vessels to support tumor growth. Historically, VEGF has been thought to signal via receptor tyrosine kinases, which are not typically considered to be G protein dependent. Here, we show that targeted knockdown of the G protein gng2 gene (Gγ2) blocks the normal angiogenic process in developing zebrafish embryos. Moreover, loss of gng2 function inhibits the ability of VEGF to promote the angiogenic sprouting of blood vessels by attenuating VEGF induced phosphorylation of phospholipase C-gamma1 (PLCγ1) and serine/threonine kinase (AKT). Collectively, these results demonstrate a novel interaction between Gγ2- and VEGF-dependent pathways to regulate the angiogenic process in a whole-animal model. Blocking VEGF function using a humanized anti-VEGF antibody has emerged as a promising treatment for colorectal, non-small lung cell, and breast cancers. However, this treatment may cause considerable side effects. Our findings provide a new opportunity for cotargeting G protein- and VEGF-dependent pathways to synergistically block pathologic angiogenesis, which may lead to a safer and more efficacious therapeutic regimen to fight cancer. (Blood. 2006;108:160-166)

scholarly journals Phytochemicals Targeting VEGF and VEGF-Related Multifactors as Anticancer Therapy

2019 ◽  
Vol 8 (3) ◽  
pp. 350 ◽  
Author(s):  
Amna Parveen ◽  
Lalita Subedi ◽  
Heung Kim ◽  
Zahra Khan ◽  
Zahra Zahra ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Anticancer Therapy ◽  
Cancer Growth ◽  
Vascular Endothelial ◽  
Vegf Signaling ◽  
Multiple Factors ◽  
Cancer Initiation ◽  
Bioactive Phytochemicals ◽  
Endothelial Growth Factor

The role of vascular endothelial growth factor (VEGF) in cancer cells is not limited to angiogenesis; there are also multiple factors, such as neuropilins (non-tyrosine kinases receptors), tyrosine kinases receptors, immunodeficiencies, and integrins, that interact with VEGF signaling and cause cancer initiation. By combating these factors, tumor progression can be inhibited or limited. Natural products are sources of several bioactive phytochemicals that can interact with VEGF-promoting factors and inhibit them through various signaling pathways, thereby inhibiting cancer growth. This review provides a deeper understanding of the relation and interaction of VEGF with cancer-promoting factors and phytochemicals in order to develop multi-targeted cancer prevention and treatment.

scholarly journals The Involvement of Angiotensin Type 1 and Type 2 Receptors in Estrogen-Induced Cell Proliferation and Vascular Endothelial Growth Factor Expression in the Rat Anterior Pituitary

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Hanna Lawnicka ◽  
Dorota Ptasinska-Wnuk ◽  
Slawomir Mucha ◽  
Jolanta Kunert-Radek ◽  
Marek Pawlikowski ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Blood Vessels ◽  
Proliferation Index ◽  
Pituitary Cells ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Rat Pituitary ◽  
Endothelial Growth Factor

The aim of our study was to examine the involvement of renin-angiotensin system (RAS) in estrogen-induced lactotropes proliferation and vascular endothelial growth factor (VEGF) expression in rat pituitary. The study was performed on Fisher 344 rats underwent 8-day treatment with diethylstilboestrol (DES). The proliferation index (PCNA) and VEGF expression in pituitary sections were estimated using immunohistochemical methods. Treatment with DES increased the number of PCNA-positive cells, VEGF-positive cells, and VEGF-positive blood vessels in pituitary. Stimulatory effect of estrogen on cell proliferation and VEGF expression in blood vessels was attenuated by losartan, PD123319, and captopril. VEGF immunoreactivity in pituitary cells of DES-treated rats was decreased by AT1 antagonist and not changed by AT2 blocker and ACE inhibitor. Our findings suggest the involvement of RAS in DES-induced cell proliferation and VEGF expression in pituitary. Both the AT1 and AT2 receptors appear to mediate the estrogen-dependent mitogenic and proangiogenic effects in rat pituitary.

scholarly journals Phospholipase Cγ Activation Drives Increased Production of Autotaxin in Endothelial Cells and Lysophosphatidic Acid-Dependent Regression

2010 ◽  
Vol 30 (10) ◽  
pp. 2401-2410 ◽  
Author(s):  
Eunok Im ◽  
Ruta Motiejunaite ◽  
Jorge Aranda ◽  
Eun Young Park ◽  
Lorenzo Federico ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Lysophosphatidic Acid ◽  
Vascular Endothelial ◽  
Additional Mechanism ◽  
Phospholipase Cγ1 ◽  
Common Substrate ◽  
Phosphoinositide 3 Kinase ◽  
Endothelial Growth Factor

ABSTRACT We previously reported that vascular endothelial growth factor (VEGF)-dependent activation of phospholipase Cγ1 (PLCγ) regulated tube stability by competing with phosphoinositide 3-kinase (PI3K) for their common substrate. Here we describe an additional mechanism by which PLCγ promoted regression of tubes and blood vessels. Namely, it increased the level of autotaxin (ATX), which is a secreted form of lysophospholipase D that produces lysophosphatidic acid (LPA). LPA promoted motility of endothelial cells, leading to disorganization/regression of tubes in vitro. Furthermore, mice that under- or overexpressed members of this intrinsic destabilization pathway showed either delayed or accelerated, respectively, regression of blood vessels. We conclude that endothelial cells can be instructed to engage a PLCγ-dependent intrinsic destabilization pathway that results in the production of soluble regression factors such as ATX and LPA. These findings are likely to potentiate ongoing efforts to prevent, manage, and eradicate numerous angiogenesis-based diseases such as proliferative diabetic retinopathy and solid tumors.

scholarly journals Identification and Characterization of Regulator of G Protein Signaling 4 (RGS4) as a Novel Inhibitor of Tubulogenesis: RGS4 Inhibits Mitogen-activated Protein Kinases and Vascular Endothelial Growth Factor Signaling

2005 ◽  
Vol 16 (2) ◽  
pp. 609-625 ◽  
Author(s):  
Allan R. Albig ◽  
William P. Schiemann
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Growth Factor ◽  
G Protein ◽  
P38 Mapk ◽  
G Protein Signaling ◽  
Vascular Endothelial ◽  
Protein Signaling ◽  
Mapk Activation ◽  
Endothelial Growth Factor

Tubulogenesis by epithelial cells regulates kidney, lung, and mammary development, whereas that by endothelial cells regulates vascular development. Although functionally dissimilar, the processes necessary for tubulation by epithelial and endothelial cells are very similar. We performed microarray analysis to further our understanding of tubulogenesis and observed a robust induction of regulator of G protein signaling 4 (RGS4) mRNA expression solely in tubulating cells, thereby implicating RGS4 as a potential regulator of tubulogenesis. Accordingly, RGS4 overexpression delayed and altered lung epithelial cell tubulation by selectively inhibiting G protein-mediated p38 MAPK activation, and, consequently, by reducing epithelial cell proliferation, migration, and expression of vascular endothelial growth factor (VEGF). The tubulogenic defects imparted by RGS4 in epithelial cells, including its reduction in VEGF expression, were rescued by overexpression of constitutively active MKK6, an activator of p38 MAPK. Similarly, RGS4 overexpression abrogated endothelial cell angiogenic sprouting by inhibiting their synthesis of DNA and invasion through synthetic basement membranes. We further show that RGS4 expression antagonized VEGF stimulation of DNA synthesis and extracellular signal-regulated kinase (ERK)1/ERK2 and p38 MAPK activation as well as ERK1/ERK2 activation stimulated by endothelin-1 and angiotensin II. RGS4 had no effect on the phosphorylation of Smad1 and Smad2 by bone morphogenic protein-7 and transforming growth factor-β, respectively, indicating that RGS4 selectively inhibits G protein and VEGF signaling in endothelial cells. Finally, we found that RGS4 reduced endothelial cell response to VEGF by decreasing VEGF receptor-2 (KDR) expression. We therefore propose RGS4 as a novel antagonist of epithelial and endothelial cell tubulogenesis that selectively antagonizes intracellular signaling by G proteins and VEGF, thereby inhibiting cell proliferation, migration, and invasion, and VEGF and KDR expression.

scholarly journals Vascular Permeability Factor/Vascular Endothelial Growth Factor Induces Lymphangiogenesis as well as Angiogenesis

2002 ◽  
Vol 196 (11) ◽  
pp. 1497-1506 ◽  
Author(s):  
Janice A. Nagy ◽  
Eliza Vasile ◽  
Dian Feng ◽  
Christian Sundberg ◽  
Lawrence F. Brown ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Blood Vessels ◽  
Vascular Permeability ◽  
Malignant Tumors ◽  
Vascular Endothelial ◽  
Vascular Permeability Factor ◽  
Immunodeficient Mice ◽  
Permeability Factor ◽  
Endothelial Growth Factor

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF, VEGF-A) is a multifunctional cytokine with important roles in pathological angiogenesis. Using an adenoviral vector engineered to express murine VEGF-A164, we previously investigated the steps and mechanisms by which this cytokine induced the formation of new blood vessels in adult immunodeficient mice and demonstrated that the newly formed blood vessels closely resembled those found in VEGF-A–expressing tumors. We now report that, in addition to inducing angiogenesis, VEGF-A164 also induces a strong lymphangiogenic response. This finding was unanticipated because lymphangiogenesis has been thought to be mediated by other members of the VPF/VEGF family, namely, VEGF-C and VEGF-D. The new “giant” lymphatics generated by VEGF-A164 were structurally and functionally abnormal: greatly enlarged with incompetent valves, sluggish flow, and delayed lymph clearance. They closely resembled the large lymphatics found in lymphangiomas/lymphatic malformations, perhaps implicating VEGF-A in the pathogenesis of these lesions. Whereas the angiogenic response was maintained only as long as VEGF-A was expressed, giant lymphatics, once formed, became VEGF-A independent and persisted indefinitely, long after VEGF-A expression ceased. These findings raise the possibility that similar, abnormal lymphatics develop in other pathologies in which VEGF-A is overexpressed, e.g., malignant tumors and chronic inflammation.

scholarly journals Scl isoforms act downstream of etsrp to specify angioblasts and definitive hematopoietic stem cells

Blood ◽  
2010 ◽  
Vol 115 (26) ◽  
pp. 5338-5346 ◽  
Author(s):  
Xi Ren ◽  
Gustavo A. Gomez ◽  
Bo Zhang ◽  
Shuo Lin
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Critical Role ◽  
Vascular Endothelial ◽  
Hematopoietic Stem ◽  
Vegf Signaling ◽  
Endothelial Growth Factor ◽  
Endothelial Development ◽  
Definitive Hematopoiesis ◽  
Runx1 Expression

Abstract Recent lineage studies suggest that hematopoietic stem cells (HSCs) may be derived from endothelial cells. However, the genetic hierarchy governing the emergence of HSCs remains elusive. We report here that zebrafish ets1-related protein (etsrp), which is essential for vascular endothelial development, also plays a critical role in the initiation of definitive hematopoiesis by controlling the expression of 2 stem cell leukemia (scl) isoforms (scl-α and scl-β) in angioblasts. In etsrp morphants, which are deficient in endothelial and HSC development, scl-α alone partially rescues angioblast specification, arterial-venous differentiation, and the expression of HSC markers, runx1 and c-myb, whereas scl-β requires angioblast rescue by fli1a to restore runx1 expression. Interestingly, when vascular endothelial growth factor (Vegf) signaling is inhibited, HSC marker expression can still be restored by scl-α in etsrp morphants, whereas the rescue of arterial ephrinb2a expression is blocked. Furthermore, both scl isoforms partially rescue runx1 but not ephrinb2a expression in embryos deficient in Vegf signaling. Our data suggest that downstream of etsrp, scl-α and fli1a specify the angioblasts, whereas scl-β further initiates HSC specification from this angioblast population, and that Vegf signaling acts upstream of scl-β during definitive hematopoiesis.

scholarly journals Convergence of VEGF and YAP/TAZ signaling: Implications for angiogenesis and cancer biology

2018 ◽  
Vol 11 (552) ◽  
pp. eaau1165 ◽  
Author(s):  
Ameer L. Elaimy ◽  
Arthur M. Mercurio
Keyword(s):  
Endothelial Cells ◽  
Tumor Cells ◽  
Cancer Biology ◽  
Vascular Endothelial ◽  
Vascular Growth ◽  
Vegf Signaling ◽  
Pathological Angiogenesis ◽  
Cytoskeletal Dynamics ◽  
Rho Family ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) stimulates endothelial cells to promote both developmental and pathological angiogenesis. VEGF also directly affects tumor cells and is associated with the initiation, progression, and recurrence of tumors, as well as the emergence and maintenance of cancer stem cells (CSCs). Studies have uncovered the importance of the transcriptional regulators YAP and TAZ in mediating VEGF signaling. For example, VEGF stimulates the GTPase activity of Rho family members and thereby alters cytoskeletal dynamics, which contributes to the activation of YAP and TAZ. In turn, YAP- and TAZ-mediated changes in gene expression sustain Rho family member activity and cytoskeletal effects to promote both vascular growth and remodeling in endothelial cells and the acquisition of stem-like traits in tumor cells. In this Review, we discuss how these findings further explain the pathophysiological roles of VEGF and YAP/TAZ, identify their connections to other receptor-mediated pathways, and reveal ways of therapeutically targeting their convergent signals in patients.

Sign in / Sign up

Export Citation Format

Share Document