scholarly journals Estrogen Deprivation and Replacement Modulate Cerebral Capillary Density with Vascular Expression of Angiogenic Molecules in Middle-Aged Female Rats

2003 ◽  
Vol 23 (2) ◽  
pp. 181-189 ◽  
Author(s):  
Subrina Jesmin ◽  
Yuichi Hattori ◽  
Ichiro Sakuma ◽  
Ming-Yue Liu ◽  
Chishimba N. Mowa ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Capillary Density ◽  
Cerebral Vessels ◽  
Female Rats ◽  
Sham Operation ◽  
Vascular Endothelial ◽  
Middle Aged ◽  
Cerebral Capillary ◽  
Endothelial Growth Factor

The effect of postmenopausal estrogen replacement therapy (ERT) on the risk or severity of cerebrovascular disorders is as yet unclear, and the evidence for flow preservation being a mechanism of estrogen neuroprotection remains elusive. The authors examined whether estrogen-mediated flow-preserving neuroprotective mechanisms, if any, may involve its angiogenic action. This study was conducted using middle-aged (44 weeks) female rats because of the importance of aging in cerebrovascular disease in women. Middle-aged female rats were subjected to sham operation, ovariectomy, or ovariectomy with ERT. The anatomic cerebral capillary morphology showed a significant reduction in the total capillary density in the frontal cortex after ovariectomy. This was associated with marked decreases in protein and gene expression of vascular endothelial growth factor and its angiogenic receptors in cerebral vessels, as demonstrated by immunohistochemistry and in situ hybridization. The expression levels of both estrogen receptor (ER) subtypes, ERα and ERβ, in cerebral vessels were significantly reduced after ovariectomy, but ERβ was more dramatically downregulated as assessed by the ERβ/ERα ratio. These ovariectomy-induced changes were completely prevented by ERT. Vascular endothelial growth factor appears to be a critical regulatory molecule for physiologic cerebral angiogenesis in middle-aged female rats and may play an important role in the flow-preserving neuroprotective action of estrogen through its angiogenic and antiapoptotic properties.

scholarly journals Estrogen Receptor-α Overexpression Suppresses 17β-Estradiol-Mediated Vascular Endothelial Growth Factor Expression and Activation of Survival Kinases

Endocrinology ◽  
2008 ◽  
Vol 149 (8) ◽  
pp. 3881-3889 ◽  
Author(s):  
Shameena Bake ◽  
Lijiang Ma ◽  
Farida Sohrabji
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Estrogen Receptor ◽  
Growth Factors ◽  
Growth Factor ◽  
Cell Line ◽  
Female Rats ◽  
High Dose ◽  
Vascular Endothelial ◽  
17Β Estradiol ◽  
Endothelial Growth Factor

Estrogen and its receptors influence growth and differentiation by stimulating the production and secretion of growth factors. Our previous studies indicate an increased expression of estrogen receptor (ER)-α and decreased growth factor synthesis in the olfactory bulb of reproductive senescent female rats as compared with young animals. The present study tests the hypothesis that abnormal overexpression of ERα contributes to decreased growth factor synthesis. We developed the HeLa-Tet-On cell line stably transfected with ERα (HTERα) that expresses increasing amounts of ERα with increasing doses of doxycycline (Dox). Increasing doses of Dox had no effect on vascular endothelial growth factor (VEGF) secretion in HTERα cells. However, in the presence of 40 nm 17β-estradiol, VEGF secretion increased in low-dose Dox-exposed HTERα cultures, which was attenuated by the ERα antagonist, 1,3-Bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]1H-pyrazole dihydrochloride. However, at high-dose Dox and, consequently, high ERα levels, estradiol failed to increase VEGF. In the HeLa X6 cell line in which the Tet-On construct is upstream of an unrelated gene (Pitx2A), estradiol failed to induce VEGF at any Dox dose. Furthermore, in the HTERα cell line, estradiol selectively down-regulates phospho-ERK2 and phospho-Akt at high ERα expression. This study clearly demonstrates that the dose of receptor critically mediates estradiol’s ability to regulate growth factors and survival kinases. The present data also support the hypothesis that 17β-estradiol treatment to an ERα overexpressing system, such as the senescent brain, could reverse the normally observed beneficial effect of estrogen.

scholarly journals 17β-Estradiol Increases Astrocytic Vascular Endothelial Growth Factor (VEGF) in Adult Female Rat Hippocampus

Endocrinology ◽  
2011 ◽  
Vol 152 (5) ◽  
pp. 1745-1751 ◽  
Author(s):  
Sharon Barouk ◽  
Tana Hintz ◽  
Ping Li ◽  
Aine M. Duffy ◽  
Neil J. MacLusky ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Adult Female ◽  
Serum Levels ◽  
Female Rats ◽  
Female Rat ◽  
Vascular Endothelial ◽  
17Β Estradiol ◽  
Endothelial Growth Factor ◽  
Vegf Protein

Vascular endothelial growth factor (VEGF) is critical to angiogenesis and vascular permeability. It is also important in the endocrine system, in which VEGF mediates the vascular effects of estrogens in target tissues such as the uterus, a response attributed to an estrogen response element on the VEGF gene. Here we asked whether 17β-estradiol increases VEGF levels in the brain. We focused on the hippocampus, in which 17β-estradiol and VEGF both have important actions, and used immunocytochemistry to evaluate VEGF protein. VEGF immunoreactivity was compared in adult female rats sampled during the estrous cycle when serum levels of 17β-estradiol peak (proestrous morning) as well as when they are low (metestrous morning). In addition, adult rats were ovariectomized and compared after treatment with 17β-estradiol or vehicle. The results demonstrated that VEGF immunoreactivity was increased when serum levels of 17β-estradiol were elevated. Confocal microscopy showed that VEGF immunofluorescence was predominantly nonneuronal, often associated with astrocytes. Glial VEGF labeling was primarily punctate rather than diffuse and labile because glial VEGF immunoreactivity was greatly reduced if tissue sections were left in an aqueous medium overnight. We conclude that VEGF protein in normal female hippocampus is primarily nonneuronal rather than neuronal and suggest that glial VEGF immunoreactivity has been underestimated by past studies with other methods because there is a labile extracellular pool. We suggest that estrogens may exert actions on female hippocampal structure and function by increasing hippocampal VEGF.

Renal vascular endothelial growth factor in neonatal obstructive nephropathy. I. Endogenous VEGF

2007 ◽  
Vol 292 (1) ◽  
pp. F158-F167 ◽  
Author(s):  
Laura E. Burt ◽  
Michael S. Forbes ◽  
Barbara A. Thornhill ◽  
Susan C. Kiley ◽  
Robert L. Chevalier
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Western Blotting ◽  
Neonatal Rat ◽  
Obstructive Nephropathy ◽  
Sham Operation ◽  
Vascular Endothelial ◽  
Neonatal Rats ◽  
Rt Pcr ◽  
Endothelial Growth Factor

Obstructive nephropathy constitutes a major cause of renal impairment in children. Chronic unilateral ureteral obstruction (UUO) impairs maturation of the developing kidney and leads to tubular apoptosis and interstitial inflammation. Vascular endothelial growth factor (VEGF) is involved in recovery from various forms of renal injury. We questioned whether the renal expression of endogenous VEGF and its receptor (VEGFR2/Flk-1) is modified by UUO in early development. Neonatal rats were subjected to partial or complete UUO or sham operation. The distribution of immunoreactive VEGF in each kidney was examined after 7, 14, or 28 days. Adult rats were also subjected to sham operation or complete UUO. Tubular VEGF increased between 14 and 28 days in sham-operated rats and in some partially obstructed neonatal rats but decreased with complete UUO. Parallel changes were found by Western blotting, but not by RT-PCR. Immunoreactive VEGF colocalized with mitochondria in proximal and distal tubules and also appeared in type A intercalated cells, glomerular vascular endothelium, and podocytes. While neonatal microvascular renal VEGFR2 receptor staining was strongly positive regardless of UUO, staining was weak in sham-operated adults but increased following UUO. Parallel changes in VEGFR2 expression were verified by RT-PCR and Western blotting. We conclude that endogenous renal VEGF is developmentally regulated in the neonatal rat and is differentially regulated by partial and complete UUO. Following UUO in the adult, the VEGF receptor is upregulated. Endogenous VEGF may serve an adaptive role in responding to tubular injury caused by UUO and may modulate adaptation by the contralateral kidney.

scholarly journals Administration of low-dose LH induces ovulation and prevents vascular hyperpermeability and vascular endothelial growth factor expression in superovulated rats

Reproduction ◽  
2004 ◽  
Vol 127 (4) ◽  
pp. 483-489 ◽  
Author(s):  
R Gómez ◽  
I Lima ◽  
C Simón ◽  
A Pellicer
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Biological Activities ◽  
Optimal Dose ◽  
Female Rats ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Ovarian Cells ◽  
High Doses ◽  
Endothelial Growth Factor

The administration, to rats, of a combination of pregnant mares serum gonadotrophin (PMSG) and human chorionic gonadotrophin (hCG) in high doses induces the ovarian hyperstimulation syndrome (OHSS) which is characterized by increased vascular permeability (VP) and simultaneous overexpression of vascular endothelial growth factor (VEGF) in ovarian cells. hCG has a longer half-life than LH and a greater biological activity, expressed in a higher incidence of complications such as OHSS. Similarly, FSH may also be related to the ovulatory changes within the follicle as there is a simultaneous surge in spontaneous cycles. The aim of this study was to compare the capacity of hCG, FSH and LH to induce ovulation and simultaneously prevent OHSS in the animal model. Immature female rats were treated with 10 IU PMSG for 4 days, and ovulation was triggered with saline, 10 IU hCG, 10 IU FSH, 10 IU LH or 60 IU LH. The number of oocytes ovulated into the tubes, VP and mRNA VEGF expression were evaluated and compared. All the hormones employed were as effective at triggering ovulation, with similar significant P values when compared with the control for which saline was used. The use of 10 IU LH resulted in significantly lower VP and VEGF expression than that seen in the groups treated with 10 IU hCG, 10 IU FSH or 60 IU LH. In conclusion, FSH and hCG, as well as a sixfold increase in LH, displayed similar biological activities, including increased VP due to excessive VEGF expression. The use of lower doses of LH produced similar rates of ovulation, while preventing the undesired changes in permeability. These experiments should therefore encourage clinicians to determine the optimal dose of LH to be employed in women in order to trigger ovulation and, at the same time, avoid the risk of OHSS.

scholarly journals Hypoxia-tolerant vascular endothelial growth factor-A (VEGF-A) and the genetic variations of VEGFA in Sherpa highlanders

2020 ◽  
Author(s):  
Yunden Droma ◽  
Takumi Kinjo ◽  
Shuhei Nozawa ◽  
Nobumitsu Kobayashi ◽  
Masanori Yasuo ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
High Altitude ◽  
Capillary Density ◽  
Tibet Plateau ◽  
Vascular Endothelial ◽  
Nucleotide Polymorphisms ◽  
High Altitudes ◽  
Tolerance To Hypoxia ◽  
Endothelial Growth Factor

AbstractSherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, partly by one of the adaptation mechanisms promoting increases of microcirculatory blood flow and capillary density at high altitude for restoring oxygen supply to tissues. Hypoxia stimulates vascular endothelial growth factor (VEGF), which is an important signaling protein involved in hypoxia-stimulated vasculogenesis and angiogenesis. Our present study included 51 Sherpas dwelling in Namche Bazaar village (3440 m) and 76 non-Sherpa lowlanders residing in Kathmandu (1300 m) in Nepal. In these participants, we measured plasma VEGF-A concentrations and genotyped five single-nucleotide polymorphisms (SNPs) of VEGFA: rs699947, rs8333061, rs1570360, and rs2010963 in the 5′-untranslated region (5′-UTR); and rs3025039 in the 3′-UTR. The average circulating VEGF-A level in Sherpas did not respond to hypoxia at the high altitude in 3440 m, remaining equivalent to the level in non-Sherpa lowlanders at low altitude. Allele discriminations for the analyzed SNPs revealed significant genetic divergences of rs699947, rs8333061, and rs2010963 in Sherpa highlanders compared with non-Sherpa lowlanders, East Asians, South Asians, and the global population; however, consistency with the indigenous Tibetan highlanders from the Tibet Plateau. On the other hand, the SNP rs3025039 in the 3′-UTR presented constant preserved genetic variation among global populations. Our findings indicated that the physiological sea-level VEGF-A concentration in Sherpa highlanders at high altitude was probably linked with the significant variations of VEGFA in Sherpas that regulate the gene expression in a manner of tolerance to hypoxia through production of the optimal biological level of VEGF-A at high altitudes. Precise angiogenesis at high altitude contributes to the adaptive levels of capillary density and microcirculation, providing efficient and effective diffusion of oxygen to tissues and representing human adaptation to high-altitude hypoxia environment.Author summarySherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, partly by one of the adaptation mechanisms promoting increases of microcirculatory blood flow and capillary density at high altitude for restoring oxygen supply to tissues. Vascular endothelial growth factor (VEGF) is mainly stimulated by hypoxia, and is an important signaling protein involved in hypoxia-stimulated vasculogenesis and angiogenesis. Interestingly, we found that the circulating VEGF-A level in Sherpa highlanders did not respond to hypoxia at high altitude. Furthermore, allele discrimination of the single nucleotide polymorphisms (SNPs) of VEGFA revealed significant divergences of rs699947, rs8333061, and rs2010963 within the VEGFA regulation region in Sherpa highlanders compared to the non-Sherpa lowlanders, East Asians, South Asians, and the global population; however, consistency with Tibetan highlanders from the Tibet Plateau. We propose that the hypoxia-tolerant circulating VEGF-A level in Sherpa highlanders is linked with the genetic variations of VEGFA, contributing to human adaptation to high-altitude hypoxic environments.

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