TY - JOUR
T1 - Hemoglobin induced NO/cGMP suppression deteriorate microcirculation via pericyte phenotype transformation after subarachnoid hemorrhage in rats
AU - Li, Qiang
AU - Chen, Yujie
AU - Li, Bo
AU - Luo, Chunxia
AU - Zuo, Shilun
AU - Liu, Xin
AU - Zhang, John H.
AU - Ruan, Huaizhen
AU - Feng, Hua
N1 - Funding Information:
This work was supported by the National Basic Research Program of China (973 Program) 2014CB541600 and the National Natural Science Foundation of China grants 81220108009, 31171069, 81501002.
PY - 2016/2/25
Y1 - 2016/2/25
N2 - Subarachnoid hemorrhage (SAH) usually results from ruptured aneurysm, but how leaked hemoglobin regulates the microcirculation in the pathophysiology of early brain injury after SAH is still unclear. In the present study, we sought to investigate the role and possible mechanism of hemoglobin induced pericyte phenotype transformation in the regulation of microcirculation after SAH. Endovascular perforation SAH rat model, brain slices and cultured pericytes were used, and intervened with endothelial nitric oxide synthase (eNOS) antagonist L-NNA and its agonist scutellarin, hemoglobin, DETA/NO (nitric oxide(NO) donor), PITO (NO scavenger), 8-Br-cGMP (cGMP analog). We found modulating eNOS regulated pericyte α-SMA phenotype transformation, microcirculation, and neurological function in SAH rats. Modulating eNOS also affected eNOS expression, eNOS activity and NO availability after SAH. In addition, we showed hemoglobins penetrated into brain parenchyma after SAH. And hemoglobins significantly reduced the microvessel diameters at pericyte sites, due to the effects of hemoglobin inducing α-SMA expressions in cultured pericytes and brain slices via inhibiting NO/cGMP pathway. In conclusion, pericyte α-SMA phenotype mediates acute microvessel constriction after SAH possibly by hemoglobin suppressing NO/cGMP signaling pathway. Therefore, by targeting the eNOS and pericyte α-SMA phenotype, our present data may shed new light on the management of SAH patients.
AB - Subarachnoid hemorrhage (SAH) usually results from ruptured aneurysm, but how leaked hemoglobin regulates the microcirculation in the pathophysiology of early brain injury after SAH is still unclear. In the present study, we sought to investigate the role and possible mechanism of hemoglobin induced pericyte phenotype transformation in the regulation of microcirculation after SAH. Endovascular perforation SAH rat model, brain slices and cultured pericytes were used, and intervened with endothelial nitric oxide synthase (eNOS) antagonist L-NNA and its agonist scutellarin, hemoglobin, DETA/NO (nitric oxide(NO) donor), PITO (NO scavenger), 8-Br-cGMP (cGMP analog). We found modulating eNOS regulated pericyte α-SMA phenotype transformation, microcirculation, and neurological function in SAH rats. Modulating eNOS also affected eNOS expression, eNOS activity and NO availability after SAH. In addition, we showed hemoglobins penetrated into brain parenchyma after SAH. And hemoglobins significantly reduced the microvessel diameters at pericyte sites, due to the effects of hemoglobin inducing α-SMA expressions in cultured pericytes and brain slices via inhibiting NO/cGMP pathway. In conclusion, pericyte α-SMA phenotype mediates acute microvessel constriction after SAH possibly by hemoglobin suppressing NO/cGMP signaling pathway. Therefore, by targeting the eNOS and pericyte α-SMA phenotype, our present data may shed new light on the management of SAH patients.
KW - Cyclic GMP/metabolism
KW - Gene Expression
KW - Pericytes/metabolism
KW - Subarachnoid Hemorrhage/genetics
KW - Signal Transduction
KW - Rats
KW - Male
KW - Nitric Oxide Synthase Type III/genetics
KW - Nitric Oxide/metabolism
KW - Microcirculation
KW - Phenotype
KW - Animals
KW - Hemoglobins/biosynthesis
KW - Enzyme Activation
KW - Actins/genetics
KW - Disease Models, Animal
UR - http://www.scopus.com/inward/record.url?scp=84959441437&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84959441437&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/807c5cde-8e6c-38d4-a26b-69fe11b9aec5/
U2 - 10.1038/srep22070
DO - 10.1038/srep22070
M3 - Article
C2 - 26911739
SN - 2045-2322
VL - 6
JO - Scientific Reports
JF - Scientific Reports
M1 - 22070
ER -