Abstract
In pulmonary arterial hypertension (PAH), lung-angioproliferation leads to increased pulmonary vascular resistance, while simultaneous myocardial microvessel loss contributes to right ventricular (RV) failure. Endothelial colony forming cells (ECFC) are highly proliferative, angiogenic cells that may contribute to either pulmonary vascular obstruction or to RV microvascular adaptation. We hypothesize ECFC phenotypes (outgrowth, proliferation, tube formation) are related to markers of disease severity in a prospective cohort-study of 33 PAH and 30 healthy subjects. ECFC were transplanted in pulmonary trunk banded rats with RV failure. The presence of ECFC outgrowth in PAH patients was associated with low RV ejection fraction, low central venous saturation and a shorter time to clinical worsening (5.4 months (0.6–29.2) vs. 36.5 months (7.4–63.4), p = 0.032). Functionally, PAH ECFC had higher proliferative rates compared to control in vitro, although inter-patient variability was high. ECFC proliferation was inversely related to RV end diastolic volume (R2 = 0.39, p = 0.018), but not pulmonary vascular resistance. Tube formation-ability was similar among donors. Normal and highly proliferative PAH ECFC were transplanted in pulmonary trunk banded rats. While no effect on hemodynamic measurements was observed, RV vascular density was restored. In conclusion, we found that ECFC outgrowth associates with high clinical severity in PAH, suggesting recruitment. Transplantation of highly proliferative ECFC restored myocardial vascular density in pulmonary trunk banded rats, while RV functional improvements were not observed.
Highlights
In pulmonary arterial hypertension (PAH) angio-proliferation, inflammation and vasoconstriction of the small arteries of the lungs progressively increase pulmonary vascular resistance (PVR) [1,2]
Patients with outgrowth of Endothelial colony forming cells (ECFC) experienced significantly earlier clinical worsening defined by hospital admittance, a decrease in exercise capacity, and the start of invasive treatment with prostaglandin or death;
To improve the understanding of the clinical significance of ECFCfunction in PAH, we reTlaoteimd pErCoFvCe tfhuenuctniodner(sit.aen.,dbilnogodofotuhtegrcoliwnitcha,ltsuibgeniffoicramnacetioonf,EaCnFdCp(rdoylisf-e)rfautniocnti)ontoinmParAkHer,swoef lruenlagtevdaEscCuFlaCr fruenmctoidoneli(ni.ge.,abnldooRdVoufutgnrcotiwonth. , Otuubre fifonrdminagtiotnh,aat nbdlopordo-loifuetrgartoiownt)htoofmEaCrkFeCrsiosfmluonreg prominent in PAH patients with a severe clinical phenotype suggests that clinical severity is related to an increased recruitment of ECFC from the bone marrow
Summary
In pulmonary arterial hypertension (PAH) angio-proliferation, inflammation and vasoconstriction of the small arteries of the lungs progressively increase pulmonary vascular resistance (PVR) [1,2]. In response to tissue damage, inflammation or hypoxia, endothelial progenitor cells (EPC) are recruited to the peri-vasculature following a gradient of cytokines and chemokines. As opposed to early outgrowth cells, ECFC appear late in culture (7–28 days) in the form of (multiple) expansive monoclonal colonies [6]. ECFC do not express immune cell markers (CD14, CD45) as opposed to early outgrowth EPC [7]. On the contrary, they express markers indicating a myeloid stem cell lineage (CD34, c-kit) and resemble endothelial cells in morphology and EC marker expression (i.e., CD144, CD31, VEGFR-2, VWF) [5,8]. It is generally believed that under physiological conditions, ECFC maintain vascular hemostasis by replacement of damaged endothelium and vascularization of ischemic tissue [9,10,11]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.