VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature

2006 ◽  
Vol 290 (2) ◽  
pp. H560-H576 ◽  
Author(s):  
Tomomi Kamba ◽  
Betty Y. Y. Tam ◽  
Hiroya Hashizume ◽  
Amy Haskell ◽  
Barbara Sennino ◽  
...  
Keyword(s):  
Blood Vessels ◽  
Kinase Inhibitor ◽  
Normal Function ◽  
Epididymal Adipose Tissue ◽  
Vegf Receptor ◽  
Adult Mice ◽  
Fenestrated Capillaries ◽  
Transmission Electron ◽  
Vegf Inhibition ◽  
Dose Dependent

Unlike during development, blood vessels in the adult are generally thought not to require VEGF for normal function. However, VEGF is a survival factor for many tumor vessels, and there are clues that some normal blood vessels may also depend on VEGF. In this study, we sought to identify which, if any, vascular beds in adult mice depend on VEGF for survival. Mice were treated with a small-molecule VEGF receptor (VEGFR) tyrosine kinase inhibitor or soluble VEGFRs for 1–3 wk. Blood vessels were assessed using immunohistochemistry or scanning or transmission electron microscopy. In a study of 17 normal organs after VEGF inhibition, we found significant capillary regression in pancreatic islets, thyroid, adrenal cortex, pituitary, choroid plexus, small-intestinal villi, and epididymal adipose tissue. The amount of regression was dose dependent and varied from organ to organ, with a maximum of 68% in thyroid, but was less in normal organs than in tumors in RIP-Tag2-transgenic mice or in Lewis lung carcinoma. VEGF-dependent capillaries were fenestrated, expressed high levels of both VEGFR-2 and VEGFR-3, and had normal pericyte coverage. Surviving capillaries in affected organs had fewer fenestrations and less VEGFR expression. All mice appeared healthy, but distinct physiological changes, including more efficient blood glucose handling, accompanied some regimens of VEGF inhibition. Strikingly, most capillaries in the thyroid grew back within 2 wk after cessation of treatment for 1 wk. Our findings of VEGF dependency of normal fenestrated capillaries and rapid regrowth after regression demonstrate the plasticity of the adult microvasculature.

Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling

2006 ◽  
Vol 290 (2) ◽  
pp. H547-H559 ◽  
Author(s):  
Fabienne Baffert ◽  
Tom Le ◽  
Barbara Sennino ◽  
Gavin Thurston ◽  
Calvin J. Kuo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Basement Membrane ◽  
Kinase Inhibitor ◽  
Vegf Receptor ◽  
Blood Capillaries ◽  
Vegf Signaling ◽  
Adult Mice ◽  
Sequence Of Events ◽  
Vegf Inhibition

The vasculature of the embryo requires vascular endothelial growth factor (VEGF) during development, but most adult blood vessels lose VEGF dependence. However, some capillaries in the respiratory tract and selected other organs of adult mice regress after VEGF inhibition. The present study sought to identify the sequence of events and the fate of endothelial cells, pericytes, and vascular basement membrane during capillary regression in mouse tracheas after VEGF signaling was blocked with a VEGF-receptor tyrosine kinase inhibitor AG-013736 or soluble receptor construct (VEGF Trap or soluble adenoviral VEGFR-1). Within 1 day, patency was lost and fibrin accumulated in some tracheal capillaries. Apoptotic endothelial cells marked by activated caspase-3 were present in capillaries without blood flow. VEGF inhibition was accompanied by a 19% decrease in tracheal capillaries over 7 days and 30% over 21 days. During this period, desmin/NG2-immunoreactive pericytes moved away from regressing capillaries onto surviving vessels. Empty sleeves of basement membrane, left behind by regressing endothelial cells, persisted for about 2 wk and served as a scaffold for vascular regrowth after treatment ended. The amount of regrowth was limited by the number of surviving basement membrane sleeves. These findings demonstrate that, after inhibition of VEGF signaling, some normal capillaries regress in a systematic sequence of events initiated by a cessation of blood flow and followed by apoptosis of endothelial cells, migration of pericytes away from regressing vessels, and formation of empty basement membrane sleeves that can facilitate capillary regrowth.

scholarly journals VEGF-dependent and PDGF-dependent dynamic neurovascular reconstruction in the neurohypophysis of adult mice

2014 ◽  
Vol 222 (1) ◽  
pp. 161-179 ◽  
Author(s):  
Eriko Furube ◽  
Tetsuya Mannari ◽  
Shoko Morita ◽  
Kazunori Nishikawa ◽  
Ayaka Yoshida ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Kinase Inhibitor ◽  
Vascular Density ◽  
Oligodendrocyte Progenitor Cells ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Ki 67 ◽  
Adult Mice ◽  
Endothelial Growth Factor

Hypothalamo-neurohypophysial system (HNS) releases arginine vasopressin (AVP) and oxytocin (OXT) from axonal terminals of the neurohypophysis (NH) into blood circulation for controlling body fluid homeostasis and lactation. Chronic osmotic and suckling stimulations have been shown to cause neurovascular and neuroglial reconstruction in the NH of adult mammals and no study has been reported for vascular dynamics. The aim of this study was to elucidate the occurrence of continuous angiogenesis and growth factor-dependent neurovascular reconstruction in the NH of adult mice. Active proliferation of endothelial cells and oligodendrocyte progenitor cells (OPCs) was observed using the immunohistochemistry of bromodeoxyuridine and Ki-67. Vascular endothelial growth factor A (VEGFA) and VEGF receptor 2 (VEGFR2 (KDR)) were highly expressed at pituicytes and endothelial cells respectively. Moreover, prominent expression of platelet-derived growth factor B (PDGFB) and PDGF receptor beta was observed at OXT-containing axonal terminals and pericytes respectively. Administration of the selective tyrosine kinase inhibitor AZD2171 for VEGFRs and STI571 for PDGFRs significantly decreased proliferation of endothelial cells and OPCs. Moreover, AZD2171 treatment decreased vascular density by facilitating apoptosis of endothelial cells and the withdrawal of its treatment led to remarkable rebound proliferation of endothelial cells, so that vascular density rapidly returned to normal levels. AZD2171 decreased the density of both AVP- and OXT-containing axonal terminals, whereas STI571 selectively decreased the density of AVP-containing ones. Thus, this study demonstrates that the signaling pathways of VEGF and PDGF are crucial mediators for determining proliferation of endothelial cells and OPCs and the density of AVP- and OXT-containing axonal terminals in the HNS.

Evidence for a Blood Ganglion Barrier in the Superior Cervical Ganglion of the Rat

1982 ◽  
Vol 40 ◽  
pp. 204-204
Author(s):  
D. M. DePace
Keyword(s):  
Blood Vessels ◽  
Superior Cervical Ganglion ◽  
Peripheral Nerves ◽  
Time Schedule ◽  
Transmission Electron ◽  
Cervical Ganglion ◽  
The Central Nervous System ◽  
Cervical Ganglia ◽  
Capillary Circulation ◽  
And Control

The majority of blood vessels in the superior cervical ganglion possess a continuous endothelium with tight junctions. These same features have been associated with the blood brain barrier of the central nervous system and peripheral nerves. These vessels may perform a barrier function between the capillary circulation and the superior cervical ganglion. The permeability of the blood vessels in the superior cervical ganglion of the rat was tested by intravenous injection of horseradish peroxidase (HRP). Three experimental groups of four animals each were given intravenous HRP (Sigma Type II) in a dosage of.08 to.15 mg/gm body weight in.5 ml of.85% saline. The animals were sacrificed at five, ten or 15 minutes following administration of the tracer. Superior cervical ganglia were quickly removed and fixed by immersion in 2.5% glutaraldehyde in Sorenson's.1M phosphate buffer, pH 7.4. Three control animals received,5ml of saline without HRP. These were sacrificed on the same time schedule. Tissues from experimental and control animals were reacted for peroxidase activity and then processed for routine transmission electron microscopy.

TIVO-3: Tivozanib in patients with advanced renal cell carcinoma (aRCC) who have progressed after treatment with axitinib.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 278-278
Author(s):  
Brian I. Rini ◽  
Sumanta K. Pal ◽  
Bernard Escudier ◽  
Michael B. Atkins ◽  
Thomas E. Hutson ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Risk Category ◽  
Vegf Receptor ◽  
Free Survival ◽  
Prior Therapy ◽  
Third Line ◽  
Line Setting ◽  
Clinical Trial Information

278 Background: Tivozanib (T) is a potent and highly selective VEGF receptor (R) tyrosine kinase inhibitor in clinical development for RCC. Axitinib is also a potent and selective VEGF-R inhibitor now commonly part of front-line aRCC treatment. The activity of T after axitinib has not been previously defined. The activity of T after prior therapy types including axitinib is of clinical relevance. Methods: The pivotal TIVO-3 study enrolled subjects with mRCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI, stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint; TKI + other) then randomized in a 1:1 ratio to T or S. The primary objective of the overall trial was to compare progression free survival (PFS) by blinded independent radiological review. Patients with prior axitinib received as monotherapy in the second or third line setting and other predefined subgroups were reviewed for outcome with T. Results: Patients treated with T after prior axitinib had a PFS of 5.5 months and an ORR of 13% compared to 3.7 months and 8% for patients treated with S. Other subgroups are presented in the table below. Clinical trial information: NCT02627963 . Conclusions: Tivozanib improved PFS vs. sorafenib in patients who have progressed after multiple VEGFR-TKIs, including patients with prior second or third line axitinib treatment. These results suggest differential activity from tivozanib and axitinib despite both being potent and selective VEGF-R inhibitors. [Table: see text]

Bevacizumab Has Differential and Dose-Dependent Effects on Glioma Blood Vessels and Tumor Cells

2011 ◽  
Vol 17 (19) ◽  
pp. 6192-6205 ◽  
Author(s):  
Louisa von Baumgarten ◽  
David Brucker ◽  
Anca Tirniceru ◽  
Yvonne Kienast ◽  
Stefan Grau ◽  
...  
Keyword(s):  
Blood Vessels ◽  
Tumor Cells ◽  
Dose Dependent

RhoA-Rho kinase mediates synergistic ET-1 and phenylephrine contraction of rat corpus cavernosum

2003 ◽  
Vol 285 (5) ◽  
pp. R1145-R1152 ◽  
Author(s):  
Christopher J. Wingard ◽  
Shahid Husain ◽  
Jan Williams ◽  
Sharita James
Keyword(s):  
Kinase Inhibitor ◽  
Corpus Cavernosum ◽  
Rho Kinase ◽  
Stress Generation ◽  
Combined Stress ◽  
Fourfold Increase ◽  
Rho Kinase Inhibitor ◽  
Tissue Homogenates ◽  
Dose Dependent ◽  
Kinase Pathway

Maintenance of the detumescent state of the penis is believed to involve the actions of several vasoconstrictors. However, our mechanistic understanding of any synergistic vasoconstrictor influences is extremely limited. We tested the hypothesis that a vasoconstrictor combination of endothelin (ET-1) and phenylephrine (PE) augments the constrictor responses in rat corporal cavernosal tissues by a mechanism involving the RhoA-Rho kinase pathway. Independently, ET-1 (1 nM-30 μM) and PE (100 nM-100 μM) both caused dose-dependent contractions of isolated rat cavernosal tissues. In combination, ET-1 (30 nM) augmented the contractile effect of PE and shifted the calculated EC50 for PE (90 ± 12 to 45 ± 5 μM). The active stress generated by cavernosal strips during the ET-1 + PE combined stimulation (4.9 ± 0.2 mN/mm2) was greater than the combined stress generated with ET-1 (0.4 ± 0.1 mN/mm2) or PE (3.3 ± 0.2 mN/mm2) stimulations alone. Blockade of ETA receptors (30 nM; A-127722) reversed the augmented stress generation and the Rho-kinase inhibitor Y-27632 differentially and dose-dependently relaxed the tissue. The combined constrictor effect was associated with a fourfold increase of RhoA in the membrane faction of the tissue homogenates. We conclude that the ET-1 + PE combination potentiate vasoconstriction through mutual activation of the RhoA-Rho kinase pathway. The interactions of these agonists likely play important roles in the maintenance of the flaccid state and contribute to some forms of erectile dysfunction.

scholarly journals Synthesis, Characterization, and Optimization of Green Silver Nanoparticles Using Neopestalotiopsis clavispora and Evaluation of Its Antibacterial, Antibiofilm, and Genotoxic Effects

2021 ◽  
Vol 5 (3) ◽  
pp. 109-122
Author(s):  
Tuğba Kahraman ◽  
Safiye Elif Korcan ◽  
Recep Liman ◽  
İbrahim Hakkı Ciğerci ◽  
Yaser Acikbas ◽  
...  
Keyword(s):  
Silver Nanoparticles ◽  
Nuclear Ribosomal Dna ◽  
Diffusion Method ◽  
Dependent Manner ◽  
Transmission Electron ◽  
Infrared Spectrophotometer ◽  
Average Size ◽  
Novel Applications ◽  
Dose Dependent

Abstract Silver nanoparticles (AgNPs) have been used in a variety of biomedical applications in the last two decades, including antimicrobial, anti-inflammatory, and anticancer treatments. The present study highlights the extracellular synthesis of silver nanoparticles AgNPs using Neopestalotiopsis clavispora MH244410.1 and its antibacterial, antibiofilm, and genotoxic properties. Locally isolated N. clavispora MH244410.1 was identified by Internal transcribed spacer (ITS) sequences of nuclear ribosomal DNA. Optimization of synthesized AgNPs was performed by using various parameters (pH (2, 4, 7, 9 and 12), temperature (25, 35 and 45 °C), and substrate concentration (0.05, 0.1, 0.15, 0.2 and 0.25 mM)). After 72 hours of incubation in dark conditions, the best condition for the biosynthesis of AgNPs was determined as 0.25 mM metal concentration at pH 12 and 35 °C. Fungal synthesized AgNPs were characterized via spectroscopic and microscopic techniques such as Fouirer Transform Infrared Spectrophotometer (FTIR), UV-Visible Spectroscopy, and Transmission Electron Microscopy (TEM). The average size of the AgNPs was determined less than 60 nm using the TEM and Zetasizer measurement system (measured in purity water suspension). The characteristic peak of AgNPs was observed at ~414 nm from UV-Vis results. Antibacterial and genotoxic activity of synthesized AgNPs (0.1, 1, and 10 ppm) were also determined by using the agar well diffusion method and in vivo Somatic Mutation and Recombination Test (SMART) in Drosophila melanogaster. AgNPs exhibited potential antimicrobial activity against all the tested bacteria (Bacillus subtilis, Staphylococcus aureus, and Pseudomonas aeruginosa) except Escherichia coli in a dose-dependent manner. AgNPs did not induce genotoxicity in the Drosophila SMART assay. 79.33, 65.47, and 41.95% inhibition of biofilms formed by P. aeruginosa were observed at 10, 1, and 0.1 ppm of AgNPs, respectively. The overall results indicate that N. clavispora MH244410.1 is a good candidate for novel applications in biomedical research.

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