Endothelin B receptor agonist, IRL-1620, enhances angiogenesis and neurogenesis following cerebral ischemia in rats

Leonard, Mary G.; Gulati, Anil

doi:10.1016/j.brainres.2013.07.002

Cited by 52 publications

(96 citation statements)

References 35 publications

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“…Although the mechanisms underlying the cooperation between ET-1 and VEGF have not been defined, data from the present study showing a concomitant down-regulation of ET-1-ET-B and VEGF angiogenic systems may support this hypothesis. Furthermore, Leonerd et al reported that the ETB receptor agonist, IRL-1620, has neuroprotective effects and enhances angiogenic and neurogenic remodeling following cerebral ischemia in rat model [21]. This report suggests that ET-1 plays a therapeutic role after cerebral ischemia through the activation of ET-B.…”

Section: Et Systemmentioning

confidence: 67%

“…ET-1 is the most potent vasoconstrictor known so far [5], and it is widely known that activation of ET-B promotes the production of eNOS via Akt (also known as protein kinase B) [21]. eNOS is also produced by the VEGF pathway via KDR and Akt, so the timedependent downregulation of the mRNA expression and protein levels of eNOS in frontal cortex may contribute to the local suppression of both VEGF and ET-1 pathway.…”

Section: Et Systemmentioning

confidence: 99%

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Concomitant Down-Regulation of Et1-Etb System and VEGF Angiogenic Signaling in the Frontal Cortex of Endotoximic Mice: A Heightened Vulnerability to Cerebral Microcirculation in Sepsis

Sonobe¹,

Jesmin²,

Shimojo³

et al. 2015

J Vasc Med Surg

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Aims: Sepsis is a disease that involves abnormal alterations in the microcirculation, with endothelial dysfunction playing a central role in the pathogenesis and mortality. The exact pathophysiology of brain dysfunction associated with sepsis remains poorly understood and experimental data are scarce. It is likely that cerebral microcirculatory alterations may play a potential role. Thus, the present study sought to investigate whether key angiogenic pathways are altered in the frontal cortexin a clinically-relevant animal model of endotoxemia/sepsis, and verify whether the alterations in angiogenic pathways affect the cerebral capillary density.Main methods: Male mice at 8 weeks of age were administered either with saline alone (control group) or 20 mg/kg lipopolysaccharide (LPS) (treatment group) at different time points (1, 3, 6, and 10 h). Microvascular alterations were determined by measuring levels of cerebral mRNA, protein levels of angiogenic factors, namely vascular endothelial growth factor (VEGF) and its receptors, endothelin-1 (ET-1) and their downstream molecules, and calculating microvascular density in frontal cortex.Key �� In the frontal cortex of the endotoxemic model, the expressions of VEGF and KDR with the downstream molecule, eNOS, were diminished sharply in a time-dependent manner, implying significant alterations in the cerebral microcirculation during sepsis. Concomitantly, ET-1, which behaves as a pro-angiogenic factor under the mediation of the ET-B receptor subtype, was similarly downregulated time-dependently. Cerebral capillary density was significantly decreased at 10 hours after LPS administration (56%, p<0.05) compared to that of control brain.�� A recent study reported a significant decrease in cerebral capillary density in a sheep model of sepsis, which is strongly associated with the progression of cerebral pathologies. The current findings are consistent with the findings with this earlier study and provide the first likely mechanisms underlying the altered microcirculation based brain dysfunction in sepsis.

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Section: Et Systemmentioning

confidence: 67%

Section: Et Systemmentioning

confidence: 99%

Concomitant Down-Regulation of Et1-Etb System and VEGF Angiogenic Signaling in the Frontal Cortex of Endotoximic Mice: A Heightened Vulnerability to Cerebral Microcirculation in Sepsis

Sonobe¹,

Jesmin²,

Shimojo³

et al. 2015

J Vasc Med Surg

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“…The power was set to 80% (β = 0.8) and the level of significance (α) used was 0.05. A sample size of 6 animals per group was determined to be sufficient to detect a 20% change in the expression of CB 1 and ET B receptors, NGF, and VEGF based on published results for the expression of these proteins [19,22,32] . Data are presented as means ± SEM.…”

Section: Discussionmentioning

confidence: 99%

“…Combined with other investigations demonstrating severe neuronal disabilities in the case of ET B deletion, it has been suggested that ET B is the primary receptor involved in CNS development [18,20,21] . Subsequently, by administration of an ET B agonist in an adult rat stroke model, Leonard et al [22] identified a relationship whereby ET B receptor expression and stimulation enhance vascular endothelial growth factor (VEGF) and neuronal growth factor (NGF) supporting neurovascular remodeling. However, pharmacological stimulation of ET B receptors during postnatal development of normal rats produced an increase in only VEGF with no change in NGF expression in the brain [19] .…”

Section: Introductionmentioning

confidence: 99%

Maternal Cannabinoid Use Alters Cannabinoid (CB<sub>1</sub>) and Endothelin (ET<sub>B</sub>) Receptor Expression in the Brains of Dams but Not Their Offspring

Amlani

Hornick²,

Cooper

et al. 2017

Dev Neurosci

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According to the 2015 National Survey on Drug Use and Health, cannabis (marijuana) is the most commonly used recreational drug in the US. Among pregnant women aged 14-55 years, 3.4% were cannabis users. Presently, little is known about the neurodevelopmental effect of cannabis use during pregnancy and/or nursing on neonates. Endothelin (ET) is essential for normal development of the central nervous system (CNS). Decreases in ET_B receptor expression correlate with a decline in nerve growth factor (NGF) and an increase in vascular endothelial growth factor (VEGF) in postnatal brain. Activation of ET_B and cannabinoid 1 (CB₁) receptors each promote neurogenesis and enhance angiogenesis, indicating that both ET and CB systems play a critical role during early CNS development. Hence the purpose of this study was to determine whether maternal CB abuse during pregnancy and lactation alters the expression of ET_B receptors, CB₁ receptors, VEGF, and NGF in the postnatal rat brain. Sixteen pregnant Sprague-Dawley rats were administered either saline or anandamide (AEA) at a dose of 3 mg/kg/day i.p. from gestational day 7 and continued through weaning on postnatal day (PND) 21. Rat pups were subdivided into 4 subgroups and sacrificed on PND 2, 7, 14, and 28. Brain tissue of the pups and dams (sacrificed on PND 21) was analyzed via Western blot for the expression of ET_B receptors, CB₁ receptors, VEGF, and NGF. AEA-exposed dams had significantly fewer live births (p = 0.027), and their pups presented with significantly lower body weights on PND 7 (p = 0.013) and PND 28 (p = 0.018). There was no significant difference noted in ET_B receptor, CB₁ receptor, NGF, or VEGF expression in the pup brains. In all pups, brain ET_B receptor expression decreased and CB₁ receptor expression increased with age. In the AEA-exposed dam brain, however, there was a decrease in ET_B receptor (p = 0.043) and an increase in CB₁ receptor expression (p = 0.033). AEA exposure during pregnancy appears to affect fetal viability and postnatal weight gain in offspring while not altering the expression patterns of ET_B receptors, CB₁ receptors, NGF, or VEGF in the pup brain. The observed trend to an increase in CB₁ receptor expression concurrent with a decrease in ET_B receptor expression in both dams and pups may point to a homeostatic regulation between these 2 systems in CNS development and neuroprotection.

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“…8 Several studies also demonstrated that vascular endothelial growth factor (VEGF), a major regulator of angiogenesis in development and many pathological conditions, promoted angiogenesis and neuronal remodeling after cerebral ischemia in rats. 9 A recent study showed that VEGF may reduce neural injury significantly and improve the neural function following SCIR injury. 10 It had been shown that endothelin has an effect on regulating the expression of VEGF and its receptors following cerebral ischemia and hind limbs IR.…”

Section: Introductionmentioning

confidence: 99%

Bosentan protects the spinal cord from ischemia reperfusion injury in rats through vascular endothelial growth factor receptors

et al. 2014

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Study design: Experimental study. Objectives: To investigate whether Bosentan, an endothelin-A/-B dual receptor antagonist, could protect neurons after spinal cord ischemia reperfusion (SCIR) injury in rats and its underlying signaling pathway. Setting: Department of Neurosurgery, the Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi Province, China. Methods: Sprague-Dawley rats were randomly divided into two groups, saline group (IRS, n ¼ 48) and Bosentan group (IRB, 5 mg kg À1 , n ¼ 48). After ischemia for 1 h with occlusion of the infrarenal aorta, spinal cord were reperfused for 6h, 12h, 24h, 3d, 5d, and 7d separately. Enzyme-linked immunosorbent assay was used to detect vascular endothelial growth factor (VEGF) in serum. Immunohistochemistry was performed to detect protein expression of VEGF, VEGF receptor 1 (FLT-1) and VEGF receptor 2 (FLK-1). Gene expressions of VEGF and its receptors were evaluated using the quantitative reverse transcription polymerase chain reaction. Results: Compared with the IRS group, gene and protein expressions of VEGF, FLT-1 and FLK-1 were significantly increased (Po0.05), so was the concentration of VEGF in plasma (Po0.05). FLK-1 was expressed on spinal cord neurons.

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Endothelin B receptor agonist, IRL-1620, enhances angiogenesis and neurogenesis following cerebral ischemia in rats

Cited by 52 publications

References 35 publications

Concomitant Down-Regulation of Et1-Etb System and VEGF Angiogenic Signaling in the Frontal Cortex of Endotoximic Mice: A Heightened Vulnerability to Cerebral Microcirculation in Sepsis

Concomitant Down-Regulation of Et1-Etb System and VEGF Angiogenic Signaling in the Frontal Cortex of Endotoximic Mice: A Heightened Vulnerability to Cerebral Microcirculation in Sepsis

Maternal Cannabinoid Use Alters Cannabinoid (CB<sub>1</sub>) and Endothelin (ET<sub>B</sub>) Receptor Expression in the Brains of Dams but Not Their Offspring

Bosentan protects the spinal cord from ischemia reperfusion injury in rats through vascular endothelial growth factor receptors

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