Fibroblast growth factors preserve blood–brain barrier integrity through RhoA inhibition after intracerebral hemorrhage in mice
Fibroblast growth factors (FGFs) maintain and promote vascular integrity; however whether FGFs protect the blood–brain barrier (BBB) after intracerebral hemorrhage (ICH) remains unexplored. In this present study, we hypothesized that exogenous FGF administration attenuates brain injury after ICH, sp...
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| Format: | Article |
| Language: | English |
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Elsevier
2012-04-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S096999611200023X |
| _version_ | 1818645471701237760 |
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| author | Bin Huang Paul R. Krafft Qingyi Ma William B. Rolland Basak Caner Tim Lekic Anatol Manaenko Mai Le Jiping Tang John H. Zhang |
| author_facet | Bin Huang Paul R. Krafft Qingyi Ma William B. Rolland Basak Caner Tim Lekic Anatol Manaenko Mai Le Jiping Tang John H. Zhang |
| author_sort | Bin Huang |
| collection | DOAJ |
| description | Fibroblast growth factors (FGFs) maintain and promote vascular integrity; however whether FGFs protect the blood–brain barrier (BBB) after intracerebral hemorrhage (ICH) remains unexplored. In this present study, we hypothesized that exogenous FGF administration attenuates brain injury after ICH, specifically by preserving endothelial adherens junctions, therefore reducing vasogenic brain edema and attenuating neurofunctional deficits in mice subjected to experimental ICH.Acid fibroblast growth factor (FGF1) or basic fibroblast growth factor (FGF2) was administered intracerebroventricularly (ICV) at 0.5 h after intrastriatal injection of bacterial collagenase (cICH) or autologous whole blood (bICH). Fibroblast growth factor receptor (FGFR) inhibitor PD173074 and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 were additionally administered with FGF2. The selective Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK) inhibitor Y27632 was independently administered at 0.5 h after cICH. Brain water content and neurofunctional deficits were evaluated at 24 and 72 h after ICH induction. Evans blue extravasation as well as Western blot analysis for the quantification of activated FGFR, Akt, Ras-related C3 botulinum toxin substrate 1 (Rac1), Ras homolog gene family member A (RhoA) and adherens junction proteins (p120-catenin, β-catenin and VE-cadherin) were conducted at 72 h post-cICH. FGF treatment reduced perihematomal brain edema and improved neurofunctional deficits at 72 h after experimental ICH (p<0.05, compared to vehicle); however, FGFR and PI3K inhibition reversed these neuroprotective effects. Exogenous FGF2 increased activated FGFR, Akt, and Rac1 but reduced activated RhoA protein expression at 72 h after cICH (p<0.05, compared to vehicle), which was reversed by FGFR and PI3K inhibition. Y27632 treatment reduced brain injury at 72 h after cICH (p<0.05, compared to vehicle) and increased the expression of catenins (p120-catenin, β-catenin). In conclusion, our findings suggest that exogenous FGF treatment reduced RhoA activity via FGFR-induced activation of the PI3K-Akt-Rac1 signaling pathway, thus preserving BBB integrity, and therefore attenuating secondary brain injury after experimental ICH in mice. |
| first_indexed | 2024-12-17T00:31:16Z |
| format | Article |
| id | doaj.art-39d16d84530f435a86e3a3236cf06b6b |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T00:31:16Z |
| publishDate | 2012-04-01 |
| publisher | Elsevier |
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| series | Neurobiology of Disease |
| spelling | doaj.art-39d16d84530f435a86e3a3236cf06b6b2022-12-21T22:10:17ZengElsevierNeurobiology of Disease1095-953X2012-04-01461204214Fibroblast growth factors preserve blood–brain barrier integrity through RhoA inhibition after intracerebral hemorrhage in miceBin Huang0Paul R. Krafft1Qingyi Ma2William B. Rolland3Basak Caner4Tim Lekic5Anatol Manaenko6Mai Le7Jiping Tang8John H. Zhang9Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA; Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USADepartment of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USADepartment of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USADepartment of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USADepartment of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USADepartment of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USADepartment of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USADepartment of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USADepartment of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA; Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA, USA; Corresponding author at: Department of Neurosurgery, Loma Linda University, Loma Linda, CA 92354, USA. Fax: +1 909 558 0119.Fibroblast growth factors (FGFs) maintain and promote vascular integrity; however whether FGFs protect the blood–brain barrier (BBB) after intracerebral hemorrhage (ICH) remains unexplored. In this present study, we hypothesized that exogenous FGF administration attenuates brain injury after ICH, specifically by preserving endothelial adherens junctions, therefore reducing vasogenic brain edema and attenuating neurofunctional deficits in mice subjected to experimental ICH.Acid fibroblast growth factor (FGF1) or basic fibroblast growth factor (FGF2) was administered intracerebroventricularly (ICV) at 0.5 h after intrastriatal injection of bacterial collagenase (cICH) or autologous whole blood (bICH). Fibroblast growth factor receptor (FGFR) inhibitor PD173074 and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 were additionally administered with FGF2. The selective Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK) inhibitor Y27632 was independently administered at 0.5 h after cICH. Brain water content and neurofunctional deficits were evaluated at 24 and 72 h after ICH induction. Evans blue extravasation as well as Western blot analysis for the quantification of activated FGFR, Akt, Ras-related C3 botulinum toxin substrate 1 (Rac1), Ras homolog gene family member A (RhoA) and adherens junction proteins (p120-catenin, β-catenin and VE-cadherin) were conducted at 72 h post-cICH. FGF treatment reduced perihematomal brain edema and improved neurofunctional deficits at 72 h after experimental ICH (p<0.05, compared to vehicle); however, FGFR and PI3K inhibition reversed these neuroprotective effects. Exogenous FGF2 increased activated FGFR, Akt, and Rac1 but reduced activated RhoA protein expression at 72 h after cICH (p<0.05, compared to vehicle), which was reversed by FGFR and PI3K inhibition. Y27632 treatment reduced brain injury at 72 h after cICH (p<0.05, compared to vehicle) and increased the expression of catenins (p120-catenin, β-catenin). In conclusion, our findings suggest that exogenous FGF treatment reduced RhoA activity via FGFR-induced activation of the PI3K-Akt-Rac1 signaling pathway, thus preserving BBB integrity, and therefore attenuating secondary brain injury after experimental ICH in mice.http://www.sciencedirect.com/science/article/pii/S096999611200023XFibroblast growth factorThrombinRac1RhoAIntracerebral hemorrhageBrain injury |
| spellingShingle | Bin Huang Paul R. Krafft Qingyi Ma William B. Rolland Basak Caner Tim Lekic Anatol Manaenko Mai Le Jiping Tang John H. Zhang Fibroblast growth factors preserve blood–brain barrier integrity through RhoA inhibition after intracerebral hemorrhage in mice Neurobiology of Disease Fibroblast growth factor Thrombin Rac1 RhoA Intracerebral hemorrhage Brain injury |
| title | Fibroblast growth factors preserve blood–brain barrier integrity through RhoA inhibition after intracerebral hemorrhage in mice |
| title_full | Fibroblast growth factors preserve blood–brain barrier integrity through RhoA inhibition after intracerebral hemorrhage in mice |
| title_fullStr | Fibroblast growth factors preserve blood–brain barrier integrity through RhoA inhibition after intracerebral hemorrhage in mice |
| title_full_unstemmed | Fibroblast growth factors preserve blood–brain barrier integrity through RhoA inhibition after intracerebral hemorrhage in mice |
| title_short | Fibroblast growth factors preserve blood–brain barrier integrity through RhoA inhibition after intracerebral hemorrhage in mice |
| title_sort | fibroblast growth factors preserve blood brain barrier integrity through rhoa inhibition after intracerebral hemorrhage in mice |
| topic | Fibroblast growth factor Thrombin Rac1 RhoA Intracerebral hemorrhage Brain injury |
| url | http://www.sciencedirect.com/science/article/pii/S096999611200023X |
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