scholarly journals Blood Vessel Patterning on Retinal Astrocytes Requires Endothelial Flt-1 (VEGFR-1)

2019 ◽  
Vol 7 (3) ◽  
pp. 18 ◽  
Author(s):  
John C. Chappell ◽  
Jordan Darden ◽  
Laura Beth Payne ◽  
Kathryn Fink ◽  
Victoria L. Bautch
Keyword(s):  
Feedback Regulation ◽  
Vascular Endothelial ◽  
Vascular Networks ◽  
Cellular Mechanisms ◽  
Negative Feedback Regulation ◽  
Retinal Astrocytes ◽  
Maximum Induction ◽  
Vessel Growth ◽  
Critical Components ◽  
Endothelial Growth Factor

Feedback mechanisms are critical components of many pro-angiogenic signaling pathways that keep vessel growth within a functional range. The Vascular Endothelial Growth Factor-A (VEGF-A) pathway utilizes the decoy VEGF-A receptor Flt-1 to provide negative feedback regulation of VEGF-A signaling. In this study, we investigated how the genetic loss of flt-1 differentially affects the branching complexity of vascular networks in tissues despite similar effects on endothelial sprouting. We selectively ablated flt-1 in the post-natal retina and found that maximum induction of flt-1 loss resulted in alterations in endothelial sprouting and filopodial extension, ultimately yielding hyper-branched networks in the absence of changes in retinal astrocyte architecture. The mosaic deletion of flt-1 revealed that sprouting endothelial cells flanked by flt-1−/− regions of vasculature more extensively associated with underlying astrocytes and exhibited aberrant sprouting, independent of the tip cell genotype. Overall, our data support a model in which tissue patterning features, such as retinal astrocytes, integrate with flt-1-regulated angiogenic molecular and cellular mechanisms to yield optimal vessel patterning for a given tissue.

Taming of the wild vessel: promoting vessel stabilization for safe therapeutic angiogenesis

2011 ◽  
Vol 39 (6) ◽  
pp. 1654-1658 ◽  
Author(s):  
Silvia Reginato ◽  
Roberto Gianni-Barrera ◽  
Andrea Banfi
Keyword(s):  
Current Knowledge ◽  
Single Gene ◽  
Therapeutic Angiogenesis ◽  
Maturation Stage ◽  
Vascular Endothelial ◽  
Cellular Regulation ◽  
Vessel Growth ◽  
Vascular Structures ◽  
Endothelial Growth Factor ◽  
Vascular Maturation

VEGF (vascular endothelial growth factor) is the master regulator of blood vessel growth. However, it displayed substantial limitations when delivered as a single gene to restore blood flow in ischaemic conditions. Indeed, uncontrolled VEGF expression can easily induce aberrant vascular structures, and short-term expression leads to unstable vessels. Targeting the second stage of the angiogenic process, i.e. vascular maturation, is an attractive strategy to induce stable and functional vessels for therapeutic angiogenesis. The present review discusses the limitations of VEGF-based gene therapy, briefly summarizes the current knowledge of the molecular and cellular regulation of vascular maturation, and describes recent pre-clinical evidence on how the maturation stage could be targeted to achieve therapeutic angiogenesis.

scholarly journals Inhibition of Corneal Neovascularization by Subconjunctival Injection of Fc-Endostatin, a Novel Inhibitor of Angiogenesis

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Junko Yoshida ◽  
Robert T. Wicks ◽  
Andrea I. Zambrano ◽  
Betty M. Tyler ◽  
Kashi Javaherian ◽  
...  
Keyword(s):  
Angiogenesis Inhibitor ◽  
Corneal Neovascularization ◽  
Subconjunctival Injection ◽  
Vascular Endothelial ◽  
Vessel Length ◽  
Treatment Groups ◽  
Significant Difference ◽  
Vessel Growth ◽  
Endothelial Growth Factor ◽  
Clinical Potential

We assessed the antiangiogenic effects of subconjunctival injection of Fc-endostatin (FcE) using a human vascular endothelial growth factor-induced rabbit corneal neovascularization model. Angiogenesis was induced in rabbit corneas through intrastromal implantations of VEGF polymer implanted 2 mm from the limbus. NZW rabbits were separated into groups receiving twice weekly subconjunctival injections of either saline; 25 mg/mL bevacizumab; 2 mg/mL FcE; or 20 mg/mL FcE. Corneas were digitally imaged at 5 time points. An angiogenesis index (AI) was calculated (vessel length (mm) × vessel number score) for each observation. All treatment groups showed a significant decrease in the vessel length and AI compared to saline on all observation days (P<0.001). By day 15, FcE 2 inhibited angiogenesis significantly better than FcE 20 (P<0.01). There was no significant difference between FcE 2 and BV, although the values trended towards significantly increased inhibition by BV. BV was a significantly better inhibitor than FcE 20 by day 8 (P<0.01). FcE was safe and significantly inhibited new vessel growth in a rabbit corneal neovascularization model. Lower concentration FcE 2 exhibited better inhibition than FcE 20, consistent with previous FcE studies referencing a biphasic dose-response curve. Additional studies are necessary to further elucidate the efficacy and clinical potential of this novel angiogenesis inhibitor.

scholarly journals Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth

2009 ◽  
Vol 106 (17) ◽  
pp. 7137-7142 ◽  
Author(s):  
Won Gil Cho ◽  
Romulo J. C. Albuquerque ◽  
Mark E. Kleinman ◽  
Valeria Tarallo ◽  
Adelaide Greco ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Surface ◽  
Mouse Models ◽  
Tissue Injury ◽  
Vascular Endothelial ◽  
Small Interfering Rnas ◽  
Vessel Growth ◽  
Interfering Rna ◽  
Endothelial Growth Factor ◽  
Tlr3 Activation

Neovascularization in response to tissue injury consists of the dual invasion of blood (hemangiogenesis) and lymphatic (lymphangiogenesis) vessels. We reported recently that 21-nt or longer small interfering RNAs (siRNAs) can suppress hemangiogenesis in mouse models of choroidal neovascularization and dermal wound healing independently of RNA interference by directly activating Toll-like receptor 3 (TLR3), a double-stranded RNA immune receptor, on the cell surface of blood endothelial cells. Here, we show that a 21-nt nontargeted siRNA suppresses both hemangiogenesis and lymphangiogenesis in mouse models of neovascularization induced by corneal sutures or hindlimb ischemia as efficiently as a 21-nt siRNA targeting vascular endothelial growth factor-A. In contrast, a 7-nt nontargeted siRNA, which is too short to activate TLR3, does not block hemangiogenesis or lymphangiogenesis in these models. Exposure to 21-nt siRNA, which we demonstrate is not internalized unless cell-permeating moieties are used, triggers phosphorylation of cell surface TLR3 on lymphatic endothelial cells and induces apoptosis. These findings introduce TLR3 activation as a method of jointly suppressing blood and lymphatic neovascularization and simultaneously raise new concerns about the undesirable effects of siRNAs on both circulatory systems.

scholarly journals Implications of Vascular Endothelial Growth Factor for Postischemic Neurovascular Remodeling

2009 ◽  
Vol 29 (10) ◽  
pp. 1620-1643 ◽  
Author(s):  
Dirk Matthias Hermann ◽  
Anil Zechariah
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Brain Plasticity ◽  
Brain Perfusion ◽  
Therapeutic Angiogenesis ◽  
Vascular Endothelial ◽  
Neurologic Recovery ◽  
Vessel Growth ◽  
Neurovascular Remodeling ◽  
Endothelial Growth Factor

Neurovascular remodeling has been recently recognized as a promising target for neurologic therapies. Hopes have emerged that, by stimulating vessel growth, it may be possible to stabilize brain perfusion, and at the same time promote neuronal survival, brain plasticity, and neurologic recovery. In this review, we outline the role of vascular endothelial growth factor (VEGF) in the ischemic brain, analyzing how this growth factor contributes to brain remodeling. Studies with therapeutic VEGF administration resulted in quite variable results depending on the route and time point of delivery. Local VEGF administration consistently enhanced neurologic recovery, whereas acute intravenous delivery exacerbated brain infarcts due to enhanced brain edema. Future studies should answer the following questions: (1) whether increased vessel density translates into improvements in blood flow in the hemodynamically compromised brain; (2) how VEGF influences brain plasticity and contributes to motor and nonmotor recovery; (3) what are the actions of VEGF not only in young animals with preserved vasculature, on which previous studies have been conducted, but also in aged animals and in animals with preexisting atherosclerosis; and (4) whether the effects of VEGF can be mimicked by pharmacological compounds or by cell-based therapies. Only on the basis of such information can more definite conclusions be made with regard to whether the translation of therapeutic angiogenesis into clinics is promising.

scholarly journals Human endometrial angiogenesis

Reproduction ◽  
2001 ◽  
pp. 181-186 ◽  
Author(s):  
CE Gargett ◽  
PA Rogers
Keyword(s):  
Strong Relationship ◽  
Human Endometrium ◽  
Endothelial Cell Proliferation ◽  
Microvascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Proliferative Phase ◽  
Vessel Growth ◽  
Capillary Plexus ◽  
Reproductive Life ◽  
Endothelial Growth Factor

Angiogenesis is the development of new microvessels from existing vessels, a process that involves microvascular endothelial cells. Physiological angiogenesis rarely occurs in adults except in the ovary and endometrium during the reproductive life of females. Angiogenesis occurs by sprouting and non-sprouting mechanisms. Since endothelial sprouts are not observed in human endometrium, we hypothesized that non-sprouting mechanisms such as intussusception and elongation are involved in endometrial angiogenesis. The demand for angiogenesis differs spatially and temporally in the endometrium: angiogenesis occurs in the basalis layer during menstruation and in the functionalis and subepithelial capillary plexus during the proliferative and early secretory stages. Most studies have failed to demonstrate a link between expression of endometrial angiogenic factors and new vessel growth. However, we demonstrated recently a strong relationship between vascular endothelial growth factor (VEGF) immunolocalized in in-travascular neutrophils and endothelial cell proliferation in each of the subepithelial capillary plexus, functionalis and basalis regions of the human endometrium. Our data also indicate that focal neutrophil VEGF has a role in the development of the subepithelial capillary plexus and functionalis microvessels during the proliferative phase of the menstrual cycle. We propose that neutrophils are an intravascular source of VEGF for vessels that undergo angiogenesis by intussusception and elongation.

scholarly journals Local network regulation of orexin neurons in the lateral hypothalamus

2011 ◽  
Vol 301 (3) ◽  
pp. R572-R580 ◽  
Author(s):  
Julia Burt ◽  
Christian O. Alberto ◽  
Matthew P. Parsons ◽  
Michiru Hirasawa
Keyword(s):  
Energy Balance ◽  
Lateral Hypothalamus ◽  
Feedback Regulation ◽  
Modern Society ◽  
Fine Tuning ◽  
Local Network ◽  
Cellular Mechanisms ◽  
Negative Feedback Regulation ◽  
Common Causes ◽  
Melanin Concentrating Hormone

Obesity and inadequate sleep are among the most common causes of health problems in modern society. Thus, the discovery that orexin (hypocretin) neurons play a pivotal role in sleep/wake regulation, energy balance, and consummatory behaviors has sparked immense interest in understanding the regulatory mechanisms of these neurons. The local network consisting of neurons and astrocytes within the lateral hypothalamus and perifornical area (LH/PFA), where orexin neurons reside, shapes the output of orexin neurons and the LH/PFA. Orexin neurons not only send projections to remote brain areas but also contribute to the local network where they release multiple neurotransmitters to modulate its activity. These neurotransmitters have opposing actions, whose balance is determined by the amount released and postsynaptic receptor desensitization. Modulation and negative feedback regulation of excitatory glutamatergic inputs as well as release of astrocyte-derived factors, such as lactate and ATP, can also affect the excitability of orexin neurons. Furthermore, distinct populations of LH/PFA neurons express neurotransmitters with known electrophysiological actions on orexin neurons, such as melanin-concentrating hormone, corticotropin-releasing factor, thyrotropin-releasing hormone, neurotensin, and GABA. These LH/PFA-specific mechanisms may be important for fine tuning the firing activity of orexin neurons to maintain optimal levels of prolonged output to sustain wakefulness and stimulate consummatory behaviors. Building on these exciting findings should shed further light onto the cellular mechanisms of energy balance and sleep-wake regulation.

scholarly journals Vascular inflammation and endothelial injury in SARS-CoV-2 infection: the overlooked regulatory cascades implicated by the ACE2 gene cluster

QJM ◽  
2020 ◽  
Author(s):  
C L Shovlin ◽  
M P Vizcaychipi
Keyword(s):  
Gene Cluster ◽  
Vascular Inflammation ◽  
Feedback Regulation ◽  
Basic Question ◽  
Negative Feedback Regulation ◽  
Antiviral Therapies ◽  
Regulatory Cascades ◽  
Life Threatening ◽  
Endothelial Homeostasis ◽  
Endothelial Growth Factor

Summary Coronavirus disease 2019 (COVID-19) has presented physicians with an unprecedented number of challenges and mortality. The basic question is why, in contrast to other ‘respiratory’ viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in such multi-systemic, life-threatening complications and a severe pulmonary vasculopathy. It is widely known that SARS-CoV-2 uses membrane-bound angiotensin-converting enzyme 2 (ACE2) as a receptor, resulting in internalization of the complex by the host cell. We discuss the evidence that failure to suppress coronaviral replication within 5 days results in sustained downregulation of ACE2 protein expression and that ACE2 is under negative-feedback regulation. We then expose openly available experimental repository data that demonstrate the gene for ACE2 lies in a novel cluster of inter-regulated genes on the X chromosome including PIR encoding pirin (quercetin 2,3-dioxygenase), and VEGFD encoding the predominantly lung-expressed vascular endothelial growth factor D. The five double-elite enhancer/promoters pairs that are known to be operational, and shared read-through lncRNA transcripts, imply that ongoing SARS-CoV-2 infection will reduce host defences to reactive oxygen species, directly generate superoxide O2·− and H2O2 (a ‘ ROS storm’), and impair pulmonary endothelial homeostasis. Published cellular responses to oxidative stress complete the loop to pathophysiology observed in severe COVID-19. Thus, for patients who fail to rapidly suppress viral replication, the newly appreciated ACE2 co-regulated gene cluster predicts delayed responses that would account for catastrophic deteriorations. We conclude that ACE2 homeostatic drives provide a unified understanding that should help optimize therapeutic approaches during the wait until safe, effective vaccines and antiviral therapies for SARS-CoV-2 are delivered.

scholarly journals Hydroxyestrogens inhibit angiogenesis in swine ovarian follicles

2008 ◽  
Vol 199 (1) ◽  
pp. 127-135 ◽  
Author(s):  
G Basini ◽  
S Bussolati ◽  
S E Santini ◽  
F Bianchi ◽  
M Careri ◽  
...  
Keyword(s):  
Follicular Fluid ◽  
Ovarian Follicle ◽  
Negative Control ◽  
Follicle Development ◽  
Vascular Endothelial ◽  
Angiogenic Potential ◽  
Vessel Growth ◽  
Negative Effect ◽  
Endothelial Growth Factor ◽  
Lines Of Evidence

The rapid, controlled, and cyclical nature of angiogenesis in the ovarian follicle suggests the potential for sex steroids to influence neovascularization. Angiogenesis is regulated by a local balance between the levels of endogenous stimulators and inhibitors. Multiple lines of evidence suggest that estrogens stimulate angiogenesis via effects on endothelial cells. However, it is of outstanding value to investigate the negative control of this process. Since the main estrogen metabolites, 2-hydroxyestradiol and 4-hydroxyestradiol (4-OHE2) have been demonstrated to function as anti-estrogen in several estrogen-dependent organs; the aim of this study was to investigate their potential involvement in the modulation of follicular angiogenesis. Hydroxyestrogens were quantified in swine follicular fluid and their effects were studied on granulosa cell vascular endothelial growth factor (VEGFA) production and tested in an angiogenesis bioassay. Our study documents that these molecules are physiologically present in swine follicular fluid and their concentrations significantly (P<0.001) increase during follicle development. Moreover, angiogenesis bioassay revealed that both hydroxyestrogens significantly (P<0.001) inhibited new vessel growth. We evidenced that the most potent negative effect is mediated by 4-OHE2. The anti-angiogenic potential of this molecule is also supported by its ability to inhibit (P<0.001) VEGFA production by granulosa cells. Increased knowledge in this area is of utmost importance for future therapeutic options to contrast infertility disorders associated with aberrant angiogenesis; this would be also very useful for the treatment of diseases characterized by disregulated angiogenesis and vascular regression.

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