دورية أكاديمية
Protective role of VEGF/VEGFR2 signaling against high fatality associated with hepatic encephalopathy via sustaining mitochondrial bioenergetics functions.
العنوان: | Protective role of VEGF/VEGFR2 signaling against high fatality associated with hepatic encephalopathy via sustaining mitochondrial bioenergetics functions. |
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المؤلفون: | Tsai CY; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. cytsai@cgmh.org.tw., Wu JCC; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan., Wu CJ; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan., Chan SHH; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. |
المصدر: | Journal of biomedical science [J Biomed Sci] 2022 Jul 03; Vol. 29 (1), pp. 47. Date of Electronic Publication: 2022 Jul 03. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: BioMed Central Country of Publication: England NLM ID: 9421567 Publication Model: Electronic Cited Medium: Internet ISSN: 1423-0127 (Electronic) Linking ISSN: 10217770 NLM ISO Abbreviation: J Biomed Sci Subsets: MEDLINE |
أسماء مطبوعة: | Publication: 2009- : London : BioMed Central Original Publication: Basel ; New York : S. Karger Medical and Scientific Publishers, c1994- |
مواضيع طبية MeSH: | Hepatic Encephalopathy* , Liver Failure, Acute*, Animals ; Male ; Membrane Potential, Mitochondrial ; Mice ; Mice, Inbred C57BL ; Mitochondria ; Vascular Endothelial Growth Factor A/genetics ; Vascular Endothelial Growth Factor Receptor-2 ; Vascular Endothelial Growth Factors |
مستخلص: | Background: The lack of better understanding of the pathophysiology and cellular mechanisms associated with high mortality seen in hepatic encephalopathy (HE), a neurological complication arising from acute hepatic failure, remains a challenging medical issue. Clinical reports showed that the degree of baroreflex dysregulation is related to the severity of HE. Furthermore, mitochondrial dysfunction in the rostral ventrolateral medulla (RVLM), a key component of the baroreflex loop that maintains blood pressure and sympathetic vasomotor tone, is known to underpin impairment of baroreflex. Realizing that in addition to angiogenic and vasculogenic effects, by acting on its key receptor (VEGFR2), vascular endothelial growth factor (VEGF) elicits neuroprotection via maintenance of mitochondrial function, the guiding hypothesis of the present study is that the VEGF/VEGFR2 signaling plays a protective role against mitochondrial dysfunction in the RVLM to ameliorate baroreflex dysregulation that underpins the high fatality associated with HE. Methods: Physiological, pharmacological and biochemical investigations were carried out in proof-of-concept experiments using an in vitro model of HE that involved incubation of cultured mouse hippocampal neurons with ammonium chloride. This was followed by corroboratory experiments employing a mouse model of HE, in which adult male C57BL/6 mice and VEGFR2 wild-type and heterozygous mice received an intraperitoneal injection of azoxymethane, a toxin used to induce acute hepatic failure. Results: We demonstrated that VEGFR2 is present in cultured neurons, and observed that whereas recombinant VEGF protein maintained cell viability, gene-knockdown of vegfr2 enhanced the reduction of cell viability in our in vitro model of HE. In our in vivo model of HE, we found that VEGFR2 heterozygous mice exhibited shorter survival rate and time when compared to wild-type mice. In C57BL/6 mice, there was a progressive reduction in VEGFR2 mRNA and protein expression, mitochondrial membrane potential and ATP levels, alongside augmentation of apoptotic cell death in the RVLM, accompanied by a decrease in baroreflex-mediated sympathetic vasomotor tone and hypotension. Immunoneutralization of VEGF exacerbated all those biochemical and physiological events. Conclusions: Our results suggest that, acting via VEGFR2, the endogenous VEGF plays a protective role against high fatality associated with HE by amelioration of the dysregulated baroreflex-mediated sympathetic vasomotor tone through sustaining mitochondrial bioenergetics functions and eliciting antiapoptotic action in the RVLM. (© 2022. The Author(s).) |
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معلومات مُعتمدة: | MOST-106-2320-B-182A-014-MY3 Ministry of Science and Technology, Taiwan; MOST-109-2320-B-182A-007-MY3 Ministry of Science and Technology, Taiwan; CMRPG8L0251-2 Chang Gung Medical Foundation |
فهرسة مساهمة: | Keywords: Acute liver failure; Apoptosis; Baroreflex dysregulation; Bioenergetics failure; Mitochondrial membrane potential; Primary neuronal culture |
المشرفين على المادة: | 0 (Vascular Endothelial Growth Factor A) 0 (Vascular Endothelial Growth Factors) EC 2.7.10.1 (KDR protein, human) EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2) |
تواريخ الأحداث: | Date Created: 20220705 Date Completed: 20220706 Latest Revision: 20220716 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC9251935 |
DOI: | 10.1186/s12929-022-00831-0 |
PMID: | 35786324 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1423-0127 |
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DOI: | 10.1186/s12929-022-00831-0 |