Effect of prepro-calcitonin gene-related peptide-expressing endothelial progenitor cells on pulmonary hypertension.
BACKGROUND
Calcitonin gene-related peptide (CGRP) is a potent smooth muscle cell proliferation inhibitor and vasodilator. It is now believed that CGRP plays an important role in maintaining a low pulmonary vascular resistance. We evaluated the therapeutic effect of intravenously administered CGRP-expressing endothelial progenitor cells (EPCs) on left-to-right shunt-induced pulmonary hypertension in rats.


METHODS
Endothelial progenitor cells were obtained from cultured human peripheral blood mononuclear cells. The genetic sequence for CGRP was subcloned into cultured EPCs by human expression plasmid. Pulmonary hypertension was established in immunodeficient rats with an abdominal aorta to inferior vena cava shunt operation. The transfected EPCs were injected through the left jugular vein at 10 weeks after the shunt operation. Mean pulmonary artery pressure and total pulmonary vascular resistance were detected with right cardiac catheterization at 4 weeks. The distribution of EPCs in the lung tissue was examined with immunofluorescence technique. Histopathologic changes in the structure of the pulmonary arteries was observed with electron microscopy and subjected to computerized image analysis.


RESULTS
The lungs of rats transplanted with CGRP-expressing EPCs demonstrated a decrease in both mean pulmonary artery pressure (17.64 +/- 0.79 versus 22.08 +/- 0.95 mm Hg; p = 0.018) and total pulmonary vascular resistance (1.26 +/- 0.07 versus 2.45 +/- 0.18 mm Hg x min/mL; p = 0.037) at 4 weeks. Immunofluorescence revealed that intravenously administered cells were incorporated into the pulmonary vasculature. Pulmonary vascular remodeling was remarkably attenuated with the administration of CGRP-expressing EPCs.


CONCLUSIONS
The transplantation of CGRP-expressing EPCs may effectively attenuate established pulmonary hypertension and exert reversal effects on pulmonary vascular remodeling. Our findings suggest that the therapy based on the combination of both CGRP transfection and EPCs may be a potentially useful strategy for the treatment of pulmonary hypertensive disorders.
Zhao
Qiang
Q
Division of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, PR China.
Liu
Zixiong
Z
Wang
Zhe
Z
Yang
Cheng
C
Liu
Jun
J
Lu
Jun
J
D000818:Animals; D030801:Animals, Genetically Modified; D001012:Aorta, Abdominal / Q000601:surgery; D001794:Blood Pressure; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics* / Q000627:therapeutic use; D018929:Cell Culture Techniques; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005822:Genetic Vectors; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000503:physiopathology*; D011498:Protein Precursors / Q000235:genetics* / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D011923:Rats, Nude; D012077:Renal Artery; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*
D011498:Protein Precursors; C076404:preprocalcitonin gene-related peptide; D015740:Calcitonin Gene-Related Peptide