title: Omega-3 polyunsaturated fatty acids enhance cerebral angiogenesis and provide long-term protection after stroke.
abstract: Stroke is a devastating neurological disorder and one of the leading causes of death and serious disability. After cerebral ischemia, revascularization in the ischemic boundary zone provides nutritive blood flow as well as various growth factors to promote the survival and activity of neurons and neural progenitor cells. Enhancement of angiogenesis and the resulting improvement of cerebral microcirculation are key restorative mechanisms and represent an important therapeutic strategy for ischemic stroke. In the present study, we tested the hypothesis that post-stroke angiogenesis would be enhanced by omega-3 polyunsaturated fatty acids (n-3 PUFAs), a major component of dietary fish oil. To this end, we found that transgenic fat-1 mice that overproduce n-3 PUFAs exhibited long-term behavioral and histological protection against transient focal cerebral ischemia (tFCI). Importantly, fat-1 transgenic mice also exhibited robust improvements in revascularization and angiogenesis compared to wild type littermates, suggesting a potential role for n-3 fatty acids in post-stroke cerebrovascular remodeling. Mechanistically, n-3 PUFAs induced upregulation of angiopoietin 2 (Ang 2) in astrocytes after tFCI and stimulated extracellular Ang 2 release from cultured astrocytes after oxygen and glucose deprivation. Ang 2 facilitated endothelial proliferation and barrier formation in vitro by potentiating the effects of VEGF on phospholipase Cγ1 and Src signaling. Consistent with these findings, blockade of Src activity in post-stroke fat-1 mice impaired n-3 PUFA-induced angiogenesis and exacerbated long-term neurological outcomes. Taken together, our findings strongly suggest that n-3 PUFA supplementation is a potential angiogenic treatment capable of augmenting brain repair and improving long-term functional recovery after cerebral ischemia.
authors.affiliation: Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA; Cell Therapy Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
authors.forename: Jiayin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Yejie
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA; Cell Therapy Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA; Cell Therapy Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hu
authors.affiliation: Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA.
authors.forename: Wenting
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Rehana K
authors.initials: RK
authors.lastname: Leak
authors.affiliation: Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA; Department of Neurosurgery and PLA Institute of Neurosurgery, Chinese PLA General Hospital, Beijing 100853, China. Electronic address: chlyz34@163.com.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA; Cell Therapy Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address: chenj2@upmc.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D018920:Coculture Techniques; D004195:Disease Models, Animal; D044943:Fatty Acid Desaturases / Q000235:genetics; D015525:Fatty Acids, Omega-3 / Q000627:therapeutic use*; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000150:complications; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009422:Nervous System Diseases / Q000209:etiology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D013997:Time Factors
chemical_list: D029742:Caenorhabditis elegans Proteins; D015525:Fatty Acids, Omega-3; D018696:Neuroprotective Agents; C466741:fat-1 protein, C elegans; D044943:Fatty Acid Desaturases; D005947:Glucose
keywords: Angiogenesis; Angiopoietin 2; Astrocyte; Neuroprotection; Omega-3 polyunsaturated fatty acids; Stroke; VEGF