Expression of Vascular Endothelial Growth Factor Receptor-2 or Tie-2 on Peripheral Blood Cells Defines Functionally Competent Cell Populations Capable of Reendothelialization

Abstract

Background— Receptor tyrosine kinases that include vascular endothelial growth factor (VEGFR)-1, VEGFR-2, and Tie-2 regulate cardiovascular development and physiological and pathological angiogenesis. We were interested in the phenotypic and functional characterization of peripheral blood cells expressing these receptors and their therapeutic potential in vascular injury. Methods and Results— VEGFR-1 + , VEGFR-2 + , and Tie-2 + cells constituted ≈3.0±0.2%, 0.8±0.5%, and 2.0±0.3%, respectively, of the total population of mononuclear cells in blood. Phenotypic analysis demonstrated that all 3 cell populations mainly expressed markers of monocytic/macrophage lineage. Only VEGFR-2 + and Tie-2 + cells phenotypically, morphologically, and functionally differentiated to endothelial cells after culture, whereas VEGFR-1 + cells did not. None of the cell types proliferated in vitro. Only freshly isolated VEGFR-2 + or Tie-2 + cells but not VEGFR-2 − or Tie-2 − cell populations significantly contributed to efficient endothelialization of balloon-injured femoral arteries of nude mice. Furthermore, these cells also differentiated into α-actin–positive smooth muscle cells. Administration of bromodeoxyuridine to animals transplanted with human endothelial progenitor cells showed that VEGFR-2 + and Tie-2 + cells proliferated in vivo. Conclusions— These data demonstrate that expression of VEGFR-2 and/or Tie-2 on peripheral blood cells defines functionally competent cell populations that proliferate in vivo and that contribute to reendothelialization. These findings may have implications for a cell-based approach in vascular diseases.

Expression of Tie-2 by Human Monocytes and Their Responses to Angiopoietin-2

“…In the present study, we show that a substantial subpopulation of CD14 ϩ monocytes (20%) in human peripheral blood express Tie-2. These data agree with that of Nowak and colleagues (27) who reported previously Tie-2 ϩ expression on 2% of total PBMC, with the majority of these Tie-2 ϩ cells being monocytes. Similarly, we found negligible levels of Tie-2 on other mononuclear cells or neutrophils (27).…”

Level of CD14+-endothelial progenitor cells is not associated with coronary artery disease or cardiovascular risk factors

“…Thus we chose these two markers as they would not involve mature endothelial cells or monocytes. Most importantly, previous studies showed that CD14 + KDR + cells exhibit the potential to differentiate into cells with endothelial characteristics both in vitro and in vivo (Nowak et al 2004;Elsheikh et al 2005). Our study showed CD14 + KDR + cells constituting approximately 2.02%±1.41% of the total population of monocytes in the blood, which is very closely to the observation of Elsheikh et al (2005) (2%±0.5%).…”

Therapeutic Potential of Endothelial Progenitor Cells in Cardiovascular Diseases

“…Oth- ers have shown the ability of transplanted EPCs to restore endothelial function in damaged vessels. 99,100 We have also demonstrated the suitability of EPC to seed prosthetic grafts. Seeding of EPCs led to rapid endothelialization of expanded polytetrafluoroethylene (ePTFE) grafts after carotid interpositional grafting.…”

“…[13][14][15][16][17][22][23][24]81,[97][98][99][100] Autologous EPC transplantation may be used to promote rapid re-endothelialization and restoration of homeostasis in blood vessels injured during revascularization procedures 22-24,97-100 or for seeding of prosthetic grafts, stents, or engineered blood vessels to create a bioactive endothelial layer. 22,23,97,98 We showed recently that transplantation of autologous PB-EPCs leads to rapid re-endothelialization of balloon-denuded rabbit carotid arteries, resulting in significant reduction of neointimal hyperplasia.…”