The synergistic therapeutic effect of hepatocyte growth factor and granulocyte colony-stimulating factor on pulmonary hypertension in rats.
Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary arterial pressure and vascular resistance. Despite advances in therapy for PAH, its treatment and prognosis remain poor. We aimed to investigate whether the transplantation of bone marrow mesenchymal stem cells (MSCs) overexpressing hepatocyte growth factor (HGF), alone or in combination with granulocyte colony-stimulating factor (G-CSF), attenuates the development of experimental monocrotaline (MCT)-induced PAH. Three weeks after MCT administration, rats were divided into the following groups: (1) untreated (PAH); (2) HGF treated; (3) MSCs administered; (4) HGF-MSCs treated; and (5) HGF-MSCs plus G-CSF treated. After 3 weeks, hemodynamic changes, histomorphology, and angiogenesis were evaluated. To elucidate the molecular mechanisms of vascular remodeling and angiogenesis, serum levels of transforming growth factor (TGF)-β and endothelin-1 (ET-1) were measured, and the gene and protein expression levels of vascular cell adhesion molecule-1 (VCAM-1) and matrix metalloproteinase-9 (MMP-9) were determined. Compared with the PAH, MSC, and G-CSF groups, the HGF and HGF+G-CSF groups exhibited significantly reduced right ventricular hypertrophy and mean pulmonary arterial pressure (P < 0.05). Histologically, vessel muscularization or thickening and collagen deposition were also significantly decreased (P < 0.05). The number of vessels in the HGF+G-CSF group was higher than that in the other groups (P < 0.05). The TGF-β and ET-1 concentrations in the plasma of pulmonary hypertensive rats were markedly lower in the HGF and HGF+G-CSF groups (P < 0.05). Furthermore, HGF induced the expression of VCAM-1, and HGF treatment together with G-CSF synergistically stimulated MMP-9 expression. Transplanted HGF-MSCs combined with G-CSF potentially offer synergistic therapeutic benefit for the treatment of PAH.
Nanlou Respiratory Disease Department, Chinese PLA General Hospital, Chinese PLA Postgraduate Medical School, Beijing, 100853, People's Republic of China.
Yinghua
Y
Guo
Longxiang
L
Su
Yinghui
Y
Li
Na
N
Guo
Lixin
L
Xie
Dong
D
Zhang
Xiaojun
X
Zhang
Hongxia
H
Li
Guizhi
G
Zhang
Yajuan
Y
Wang
Changting
C
Liu
D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000097:blood; D015316:Genetic Therapy / Q000379:methods*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000503:physiopathology / Q000628:therapy*; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000097:blood; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D066253:Vascular Remodeling / Q000187:drug effects
D019332:Endothelin-1; C066855:HGF protein, human; D016212:Transforming Growth Factor beta; D019010:Vascular Cell Adhesion Molecule-1; D016179:Granulocyte Colony-Stimulating Factor; D017228:Hepatocyte Growth Factor; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat