scholarly journals The SK3 channel promotes placental vascularization by enhancing secretion of angiogenic factors

2014 ◽  
Vol 307 (10) ◽  
pp. E935-E943 ◽  
Author(s):  
Cara C. Rada ◽  
Grace Murray ◽  
Sarah K. England
Keyword(s):  
Growth Factor ◽  
Vascular Function ◽  
Fetal Loss ◽  
High Rate ◽  
Angiogenic Factor ◽  
Soluble Form ◽  
Vegf Receptor ◽  
Wild Type ◽  
Placental Perfusion ◽  
Sk3 Channel

Proper placental perfusion is essential for fetal exchange of oxygen, nutrients, and waste with the maternal circulation. Impairment of uteroplacental vascular function can lead to pregnancy complications, including preeclampsia and intrauterine growth restriction (IUGR). Potassium channels have been recognized as regulators of vascular proliferation, angiogenesis, and secretion of vasoactive factors, and their dysfunction may underlie pregnancy-related vascular diseases. Overexpression of one channel in particular, the small-conductance calcium-activated potassium channel 3 (SK3), is known to increase vascularization in mice, and mice overexpressing the SK3 channel (SK3T/T mice) have a high rate of fetal demise and IUGR. Here, we show that overexpression of SK3 causes fetal loss through abnormal placental vascularization. We previously reported that, at pregnancy day 14, placentas isolated from SK3T/T mice are smaller than those obtained from wild-type mice. In this study, histological analysis reveals that SK3T/− placentas at this stage have abnormal placental morphology, and microcomputed tomography shows that these placentas have significantly larger and more blood vessels than those from wild-type mice. To identify the mechanism by which these vascularization defects occur, we measured levels of vascular endothelial growth factor (VEGF), placental growth factor, and the soluble form of VEGF receptor 1 (sFlt-1), which must be tightly regulated to ensure proper placental development. Our data reveal that overexpression of SK3 alters systemic and placental ratios of the angiogenic factor VEGF to antiangiogenic factor sFlt-1 throughout pregnancy. Additionally, we observe increased expression of hypoxia-inducing factor 2α in SK3T/− placentas. We conclude that the SK3 channel modulates placental vascular development and fetal health by altering VEGF signaling.

106 ANGIOGENIC FACTOR mRNA EXPRESSION IN FETAL MEMBRANES IN EARLY PREGNANT SHEEP

2009 ◽  
Vol 21 (1) ◽  
pp. 153
Author(s):  
M. L. Johnson ◽  
L. P. Reynolds ◽  
M. A. Minten ◽  
P. P. Borowicz ◽  
D. A. Redmer ◽  
...  
Keyword(s):  
Growth Factor ◽  
Vascular Development ◽  
Fetal Loss ◽  
Angiogenic Factor ◽  
Fetal Membranes ◽  
Detailed Knowledge ◽  
Placental Development ◽  
Vegf Mrna ◽  
Placental Angiogenesis ◽  
Pregnant Sheep

Maternal and fetal placental development may be compromised by use of assisted reproductive techniques, including cloning, resulting in poor placental angiogenesis and subsequent high embryonic/fetal loss (Palmieri et al. 2007 Placenta 28, 577–584). Before changes in vascular development in placenta from compromised pregnancies can be understood, a detailed knowledge of regulation of angiogenesis in placental tissues from normal pregnancies is necessary. Therefore, this study determined the expression pattern of mRNA for several angiogenic factors and their receptors: vascular endothelial growth factor (VEGF) and receptor (R) 1 and 2; basic fibroblast growth factor (FGF2) and FGFRIIIc; angiopoietin (ANGPT) 1 and 2 and ANGPTR (Tie2); endothelial nitric oxide synthase (eNOS) and NO receptor GUCY1B3 in fetal membranes (FM; fetal placenta) collected on Days 16, 18, 20, 22, 24, 26, 28, and 30 after mating (n = 5 to 8/day). Fetal membranes were snap frozen for evaluation of gene expression using quantitative, real-time RT-PCR. VEGF mRNA was increased (P < 0.05) 2-fold on Days 28 and 30 compared with Days 16, 18, and 20, whereas VEGFR1 mRNA increased (P < 0.05) 25- to 50-fold on Days 28 and 30 compared with Day 16, and VEGFR2 mRNA was greatest (P < 0.05) on Day 22 compared with Days 16, 18, 28, and 30. FGF2 mRNA was 4-fold greater (P < 0.05) on Day 22 compared with Day 16; however, FGF2RIIIc was unchanged from Day 16 through 30. eNOS mRNA was greatest (P < 0.05) on Days 22 and 24 compared with Days 16 and 18, but GUCY1B3 mRNA was greatest (P < 0.05) on Day 18 compared with Days 20, 24, and 28. ANGPT1 mRNA increased (P < 0.05) 40-fold by Days 28 and 30 compared with Days 16 and 18. ANGPT2 mRNA was undetectable on Day 16, and increased (P < 0.05) 5-fold from Days 18 through 30. ANGPTR mRNA was greatest (P < 0.05) on Days 22 and 24 compared with Days 16 and 18. This description of expression of factors potentially regulating early placental angiogenesis during normal pregnancy in sheep will provide the foundation for understanding the dramatic increases in capillary cell proliferation and capillary size we have previously observed (unpublished) and for determining whether placental vascular development is altered in compromised pregnancies. USDA-NRI grant 2007-01215 to LPR and ATGB; NIH grant HL64141 to LPR and DAR; ND EPSCoR AURA grant to ATGB and MAM; ND Space Grant Fellowship Program award to MAM; and NIH grant P20 RR016741 (INBRE program of the NCRR, NIH).

ANGIOGENIC IMBALANCES IN THE PATHOGENESIS OF PREGNANCY COMPLICATIONS

2014 ◽  
Vol 25 (1) ◽  
pp. 42-58
Author(s):  
JIMMY ESPINOZA
Keyword(s):  
Pregnancy Complications ◽  
Angiogenic Factors ◽  
Angiogenic Factor ◽  
Soluble Form ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Maternal Circulation ◽  
Soluble Endoglin ◽  
Endothelial Growth Factor

Endothelial cell proliferation and survival require continuous low levels of vascular endothelial growth factor (VEGF). The bioavailability of this angiogenic factor appears to be regulated by anti-angiogenic factors, including the soluble form of VEGF receptor 1 (sFlt-1) in the non-pregnant and pregnant states. During pregnancy a VEGF antagonist (sFlt-1) and other anti-angiogenic factors, including soluble endoglin (s-Eng), are produced by the human placenta and released into the maternal circulation; an excess of these anti-angiogenic factors can lead into angiogenic imbalances and pregnancy complications. This is important because regulation of VEGF action on angiogenic balances appears to be essential for a successful pregnancy.

scholarly journals VEGF is a chemoattractant for FGF-2–stimulated neural progenitors

2003 ◽  
Vol 163 (6) ◽  
pp. 1375-1384 ◽  
Author(s):  
Huanxiang Zhang ◽  
Laszlo Vutskits ◽  
Michael S. Pepper ◽  
Jozsef Z. Kiss
Keyword(s):  
Nervous System ◽  
Growth Factor ◽  
Neural Progenitors ◽  
Angiogenic Factor ◽  
Fibroblast Growth Factor 2 ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Guidance Cue ◽  
Endothelial Growth Factor ◽  
Chemotactic Effect

Mmigration of undifferentiated neural progenitors is critical for the development and repair of the nervous system. However, the mechanisms and factors that regulate migration are not well understood. Here, we show that vascular endothelial growth factor (VEGF)-A, a major angiogenic factor, guides the directed migration of neural progenitors that do not display antigenic markers for neuron- or glia-restricted precursor cells. We demonstrate that progenitor cells express both VEGF receptor (VEGFR) 1 and VEGFR2, but signaling through VEGFR2 specifically mediates the chemotactic effect of VEGF. The expression of VEGFRs and the chemotaxis of progenitors in response to VEGF require the presence of fibroblast growth factor 2. These results demonstrate that VEGF is an attractive guidance cue for the migration of undifferentiated neural progenitors and offer a mechanistic link between neurogenesis and angiogenesis in the nervous system.

scholarly journals Overexpression of the SK3 channel alters vascular remodeling during pregnancy, leading to fetal demise

2012 ◽  
Vol 303 (7) ◽  
pp. E825-E831 ◽  
Author(s):  
Cara C. Rada ◽  
Stephanie L. Pierce ◽  
Daniel W. Nuno ◽  
Kathy Zimmerman ◽  
Kathryn G. Lamping ◽  
...  
Keyword(s):  
Cardiovascular System ◽  
Vascular Remodeling ◽  
Fetal Loss ◽  
Wild Type ◽  
Fetal Outcomes ◽  
Systolic Volume ◽  
Healthy Pregnancy ◽  
Channel Expression ◽  
End Systolic Volume ◽  
Sk3 Channel

The maternal cardiovascular system undergoes hemodynamic changes during pregnancy via angiogenesis and vasodilation to ensure adequate perfusion of the placenta. Improper vascularization at the maternal-fetal interface can cause pregnancy complications and poor fetal outcomes. Recent evidence indicates that small conductance Ca2+-activated K+ channel subtype 3 (SK3) contributes to vascular remodeling during pregnancy, and we hypothesized that abnormal SK3 channel expression would alter the ability of the maternal cardiovascular system to adapt to pregnancy demands and lead to poor fetal outcomes. We investigated this hypothesis using transgenic Kcnn3tm1Jpad/Kcnn3tm1Jpad (SK3T/T) mice that overexpress the channel. Isolated pressurized uterine arteries from nonpregnant transgenic SK3T/T mice had larger basal diameters and decreased agonist-induced constriction than those from their wild-type counterparts; however, non-receptor-mediated depolarization remained intact. In addition to vascular changes, heart rates and ejection fraction were increased, whereas end systolic volume was reduced in SK3T/T mice compared with their wild-type littermates. Uterine sonography of the fetuses on pregnancy day 14 showed a significant decrease in fetal size in SK3T/T compared with wild-type mice; thus, SK3T/T mice displayed an intrauterine growth-restricted phenotype. The SK3T/T mice showed decreased placental thicknesses and higher incidence of fetal loss, losing over half of their complement of pups by midgestation. These results establish that the SK3 channel contributes to both maternal and fetal outcomes during pregnancy and point to the importance of SK3 channel regulation in maintaining a healthy pregnancy.

scholarly journals Vascular Endothelial Growth Factor A (VEGF-A) Is Involved in Guidance of VEGF Receptor-Positive Cells to the Anterior Portion of Early Embryos

2005 ◽  
Vol 25 (1) ◽  
pp. 355-363 ◽  
Author(s):  
Sachie Hiratsuka ◽  
Yuki Kataoka ◽  
Kazuki Nakao ◽  
Kenji Nakamura ◽  
Shunichi Morikawa ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Wild Type ◽  
Anterior Portion ◽  
Whole Embryo Culture ◽  
Posterior Portion ◽  
Hematopoietic Stem ◽  
Endothelial Growth Factor

ABSTRACT The hemangioblast in the mesoderm gives rise to both angioblasts and hematopoietic stem cells. The movement of hemangioblast precursor cells in the fetal trunk is a critical event in early embryogenesis. Vascular endothelial growth factor (VEGF) signaling is likely involved in this migration given the partial disturbance of VEGF receptor (VEGFR)-positive cell accumulation and migration in VEGFR2 null mice or mice with a truncated VEGFR1. However, it is not clear how the VEGF system regulates this migration or its direction. We show here that the expression of VEGF-A is dominant in the anterior portion of the embryo, whereas VEGFR1 and VEGFR2 are expressed in the posterior portion of the embryo. An inhibitor of VEGFR kinase blocked the migration of VEGFR-positive cells in a whole-embryo culture system. In addition, VEGFR-positive cells migrated toward a VEGFR1- or VEGFR2-specific ligand in vitro. Furthermore, VEGFR-positive cells derived from wild-type or VEGFR2+/− mice moved rapidly anteriorly, whereas cells derived from VEGFR2+/− mice carrying a truncated VEGFR1 [VEGFR1(TM-TK)−/−] migrated little when injected into wild-type mice. These results suggest that the VEGF-A protein concentrated in the anterior region plays an important role in the guidance of VEGFR-positive cells from the posterior portion to the head region by interacting with VEGFR in the mouse embryo.

scholarly journals Distinct Angiogenic Mediators Are Required for Basic Fibroblast Growth Factor– and Vascular Endothelial Growth Factor–induced Angiogenesis: The Role of Cytoplasmic Tyrosine Kinase c-Abl in Tumor Angiogenesis

2008 ◽  
Vol 19 (5) ◽  
pp. 2278-2288 ◽  
Author(s):  
Wei Yan ◽  
Brooke Bentley ◽  
Rong Shao
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tumor Angiogenesis ◽  
Kinase Inhibitor ◽  
Ectopic Expression ◽  
Tumor Xenograft ◽  
Vegf Receptor ◽  
Wild Type ◽  
Kinase C ◽  
Type C

Signaling pathways engaged by angiogenic factors bFGF and VEGF in tumor angiogenesis are not fully understood. The current study identifies cytoplasmic tyrosine kinase c-Abl as a key factor differentially mediating bFGF- and VEGF-induced angiogenesis in microvascular endothelial cells. STI571, a c-Abl kinase inhibitor, only inhibited bFGF- but not VEGF-induced angiogenesis. bFGF induced membrane receptor cooperation between integrin β3 and FGF receptor, and triggered a downstream cascade including FAK, c-Abl, and MAPK. This signaling pathway is different from one utilized by VEGF that includes integrin β5, VEGF receptor-2, Src, FAK, and MAPK. Ectopic expression of wild-type c-Abl sensitized angiogenic response to bFGF, but kinase dead mutant c-Abl abolished this activity. Furthermore, the wild-type c-Abl enhanced angiogenesis in both Matrigel implantation and tumor xenograft models. These data provide novel insights into c-Abl's differential functions in mediating bFGF- and VEGF-induced angiogenesis.

Vascular Endothelial Growth Factor-B in Physiology and Disease

2014 ◽  
Vol 94 (3) ◽  
pp. 779-794 ◽  
Author(s):  
Maija Bry ◽  
Riikka Kivelä ◽  
Veli-Matti Leppänen ◽  
Kari Alitalo
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Proteolytic Processing ◽  
Metabolic Effects ◽  
Soluble Form ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Factor B ◽  
Vascular Growth Factor ◽  
Endothelial Growth Factor

Vascular endothelial growth factor-B (VEGF-B), discovered over 15 years ago, has long been seen as one of the more ambiguous members of the VEGF family. VEGF-B is produced as two isoforms: one that binds strongly to heparan sulfate in the pericellular matrix and a soluble form that can acquire binding via proteolytic processing. Both forms of VEGF-B bind to VEGF-receptor 1 (VEGFR-1) and the neuropilin-1 (NRP-1) coreceptor, which are expressed mainly in blood vascular endothelial cells. VEGF-B-deficient mice and rats are viable without any overt phenotype, and the ability of VEGF-B to induce angiogenesis in most tissues is weak. This has been a puzzle, as the related placenta growth factor (PlGF) binds to the same receptors and induces angiogenesis and arteriogenesis in a variety of tissues. However, it seems that VEGF-B is a vascular growth factor that is more tissue specific and can have trophic and metabolic effects, and its binding to VEGFR-1 shows subtle but important differences compared with that of PlGF. VEGF-B has the potential to induce coronary vessel growth and cardiac hypertrophy, which can protect the heart from ischemic damage as well as heart failure. In addition, VEGF-B is abundantly expressed in tissues with highly active energy metabolism, where it could support significant metabolic functions. VEGF-B also has a role in neuroprotection, but unlike other members of the VEGF family, it does not have a clear role in tumor progression. Here we review what is hitherto known about the functions of this growth factor in physiology and disease.

scholarly journals Antiphospholipid and antioangiogenic activity in females with recurrent miscarriage and antiphospholipid syndrome

2016 ◽  
Vol 54 (5) ◽  
pp. 577-583 ◽  
Author(s):  
Hector F Pelusa ◽  
Eleonora Pezzarini ◽  
Cecilia L Basiglio ◽  
Jorge Musuruana ◽  
Mariela Bearzotti ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Antiphospholipid Syndrome ◽  
Lupus Anticoagulant ◽  
Recurrent Miscarriage ◽  
Fetal Loss ◽  
Annexin V ◽  
Soluble Form ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Background Antiphospholipid syndrome is an autoimmune disease characterized by thrombosis, fetal losses and thrombocytopenia associated to antiphospholipid antibodies. They are directed to phospholipids, such as cardiolipins (anticardiolipin) and lupus anticoagulant or to complexes formed by phospholipids and protein cofactors, such as β2 glycoprotein 1 (a-β2GP1) and annexin V (a-annexin V). These auto-antibodies may be considered as a family of antibodies involved in thrombotic events and antiphospholipid activity. On the other hand, some proangiogenic factors are involved in the normal development of placental vasculature, such as the vascular endothelial growth factor. Overexpression of vascular endothelial growth factor receptor in its soluble form (sVEGFR-1) has been associated to a higher antiangiogenic activity. Our aim was to analyse the association between anticardiolipin, lupus anticoagulant, a-β2GP1, a-annexin V and sVEGFR-1 with recurrent miscarriage before week 10 of gestation in females with antiphospholipid syndrome. Methods We studied 24 females (primary or secondary antiphospholipid syndrome), who were divided into two groups: females with recurrent miscarriage before week 10 of gestation (M; n = 12) and females with no history of fetal loss (NM; n = 12). Anticardiolipin, a-β2GP1, a-annexin V and sVEGF-R1 concentrations were assessed by ELISA, while lupus anticoagulant was assessed by screening and confirmatory tests. Results A significant association was observed between the number of positive biomarkers and the belonging group ( P < 0.05). Besides, a positive result for lupus anticoagulant and a-β2GP1 was found to be significantly associated to the M group ( P < 0.05). Conclusions Lupus anticoagulant and a-β2GP1 may be implicated in pregnancies complicated by recurrent miscarriage in females with antiphospholipid syndrome.

scholarly journals Distinct Patterns of Cytokine and Angiogenic Factor Modulation and Markers of Benefit for Vandetanib and/or Chemotherapy in Patients With Non–Small-Cell Lung Cancer

2010 ◽  
Vol 28 (2) ◽  
pp. 193-201 ◽  
Author(s):  
Emer O. Hanrahan ◽  
Heather Y. Lin ◽  
Edward S. Kim ◽  
Shaoyu Yan ◽  
Danny Z. Du ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Unmet Need ◽  
Small Cell ◽  
Angiogenic Factor ◽  
Vegf Receptor ◽  
Small Cell Lung ◽  
Progression Risk

Purpose There is an unmet need for biomarkers for identifying patients likely to benefit from anticancer treatments, selecting dose, and understanding mechanisms of resistance. Plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptor 2 (sVEGFR-2) are known to be modulated by VEGF pathway inhibitors. It is unknown whether chemotherapy or VEGFR inhibitor/chemotherapy combinations induce changes in these or other cytokines and angiogenic factors (CAFs) and whether such changes could be markers of benefit. Methods Thirty-five plasma CAFs were analyzed using multiplexed bead arrays and enzyme-linked immunosorbent assays from 123 patients with non–small-cell lung cancer in a randomized phase II study who received vandetanib, a VEGFR and epidermal growth factor receptor inhibitor, monotherapy carboplatin and paclitaxel (CP), or the combination (VCP). Changes in CAFs at days 8, 22, and 43 from baseline were correlated with progression risk. Results VEGF increased and sVEGFR-2 decreased by day 43 in the vandetanib arm, whereas a distinct pattern was observed in the CP and VCP arms, with significant decreases in interleukin (IL) -12, IL-1 receptor antagonist, and matrix metalloproteinase 9 (MMP-9) and increased macrophage chemoattractant protein 1. In each treatment arm, changes in different markers were associated with progression risk. For example, increases in IL-8 with VCP, MMP-9 with CP, and VEGF with vandetanib monotherapy were associated with increased progression risk, and increase in intercellular adhesion molecule 1 with vandetanib was associated with decreased risk. Conclusion Vandetanib and chemotherapy treatment led to distinct patterns of CAF changes; the combination resembled chemotherapy alone. Changes in specific CAFs correlated with clinical outcome, but markers differed for each treatment arm. CAF profiling may provide insights into the biologic effects of treatment and identify drug-specific markers of activity and clinical benefit.

Statins: A Conceivable Remedial Role for the Regulation of Cancer Progression

2019 ◽  
Vol 15 (2) ◽  
pp. 131-145
Author(s):  
Gajanan V. Sherbet
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Tumour Growth ◽  
Cell Function ◽  
Mevalonate Pathway ◽  
Biological Effects ◽  
Vegf Receptor ◽  
Mesenchymal Transition ◽  
Cancer Management ◽  
Metabolic Role

The mevalonate pathway (also known as the cholesterol biosynthesis pathway) plays a crucial metabolic role in normal cell function as well as in the pathological environment. It leads to the synthesis of sterol and non-sterol isoprenoid biomolecules which subserve a variety of cellular functions. It is known to be deregulated in many disease processes. Statins and bisphosphonates are prominent inhibitors of the mevalonate pathway. They inhibit cell proliferation and activate apoptotic signalling and suppress tumour growth. Statins subdue metastatic spread of tumours by virtue of their ability to suppress invasion and angiogenesis. The induction of autophagy is another feature of statin effects that could contribute to the suppression of metastasis. Herein highlighted are the major signalling systems that statins engage to generate these biological effects. Statins can constrain tumour growth by influencing the expression and function of growth factor and receptor systems. They may suppress epithelial mesenchymal transition with resultant inhibition of cell survival signalling, together with the inhibition of cancer stem cell generation, and their maintenance and expansion. They can suppress ER (oestrogen receptor)-α in breast cancer cells. Statins have been implicated in the activation of the serine/threonine protein kinase AMPK (5&#039; adenosine monophosphate-activated protein) leading to the suppression of cell proliferation. Both statins and bisphosphonates can suppress angiogenic signalling by HIF (hypoxia- inducible factor)-1/eNOS (endothelial nitric oxide synthase) and VEGF (vascular endothelial growth factor)/VEGFR (VEGF receptor). Statins have been linked with improvements in disease prognosis. Also attributed to them is the ability of cancer prevention and reduction of risk of some forms of cancer. The wide spectrum of cancer associated events which these mevalonate inhibitors appear to influence would suggest a conceivable role for them in cancer management. However, much deliberation is warranted in the design and planning of clinical trials, their scope and definition of endpoints, modes risk assessment and the accrual of benefits.

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