- 作者: Ching-Yi Tsai, Jacqueline C. C. Wu, Chiung-Ju Wu & Samuel H. H. Chan
- 作者服務機構: Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- 中文摘要:
- 英文摘要:
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 barorefex dysregulation is related to
the severity of HE. Furthermore, mitochondrial dysfunction in the rostral ventrolateral medulla (RVLM), a key compo‑
nent of the barorefex loop that maintains blood pressure and sympathetic vasomotor tone, is known to underpin
impairment of barorefex. Realizing that in addition to angiogenic and vasculogenic efects, by acting on its key recep‑
tor (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 barorefex dysregulation that underpins the high fatality associ‑
ated 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 azox‑
ymethane, 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 apop‑
totic cell death in the RVLM, accompanied by a decrease in barorefex-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 barorefex-mediated sympathetic vasomotor tone
through sustaining mitochondrial bioenergetics functions and eliciting antiapoptotic action in the RVLM - 中文關鍵字:
- 英文關鍵字: Acute liver failure, Primary neuronal culture, Mitochondrial membrane potential, Bioenergetics failure, Apoptosis, Barorefex dysregulation