title: TGF-β1 prevents blood-brain barrier damage and hemorrhagic transformation after thrombolysis in rats.
abstract: Transforming growth factor-beta1 (TGF-β1) is well known to promote extracellular matrix accumulation. Recent studies demonstrated that TGF-β1 protects against blood-brain barrier (BBB) disruption in the condition of inflammatory pain and stroke. In the present study, we investigated whether TGF-β1 can maintain BBB integrity and prevent hemorrhagic transformation (HT) after recombinant tissue plasminogen activator (rt-PA) treatment in a rat model of thromboembolic middle cerebral artery occlusion (MCAO). Three hours after MCAO, rats were given saline, rt-PA alone or rt-PA combined with TGF-β1 intravenously. Animals were sacrificed 24h after surgery. HT was calculated as hemorrhagic score. Evans blue dye extravasation was measured for BBB disruption. Basement membrane damage was observed by electron microscopy and quantified by collagen IV and laminin immunostaining. Gelatin zymography was used to measure the activities of matrix metalloproteinase (MMP)-2 and MMP-9. Western blot was performed for the expressions of MMP-2, MMP-9 and plasminogen activator inhibitor type-1 (PAI-1). Rats treated with rt-PA showed elevations in basement membrane damage, BBB disruption and HT. These phenomena were reduced in rats treated by TGF-β1. We also showed that TGF-β1 inhibited rt-PA mediated induction of MMP-2 and MMP-9. Meanwhile, TGF-β1 upregulated PAI-1 expression which was reduced by rt-PA. Taken together, these results suggest that TGF-β1 can reduce rt-PA induced basement membrane degradation, BBB disruption and HT. One possible mechanism is associated with the elevation of PAI-1. Suppression of MMP-2 and MMP-9 elevated by rt-PA may be another mechanism contributing to the protective effects of TGF-β1.
authors.affiliation: Department of Geratology, the First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing 210029, Jiangsu Province, China.
authors.forename: Yingyuan
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, China.
authors.forename: Xinfeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Geratology, the First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing 210029, Jiangsu Province, China.
authors.forename: Weixian
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Geratology, the First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing 210029, Jiangsu Province, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, China.
authors.forename: Gelin
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Geratology, the First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing 210029, Jiangsu Province, China.
authors.forename: Yanying
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Geratology, the First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing 210029, Jiangsu Province, China. Electronic address: myp@njmu.edu.cn.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Ma
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology; D005343:Fibrinolytic Agents / Q000633:toxicity*; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D020300:Intracranial Hemorrhages / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000209:etiology / Q000517:prevention & control*; D015912:Thrombolytic Therapy / Q000009:adverse effects*; D010959:Tissue Plasminogen Activator / Q000633:toxicity*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D005343:Fibrinolytic Agents; D017395:Plasminogen Activator Inhibitor 1; D053773:Transforming Growth Factor beta1; D010959:Tissue Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: Basement membrane; Blood–brain barrier; Hemorrhagic transformation; Middle cerebral artery occlusion; Thrombolysis; Transforming growth factor-beta1