Angiogenesis and vasculogenesis: inducing the growth of new blood vessels and wound healing by stimulation of bone marrow-derived progenitor cell mobilization and homing

Abstract

During embryonic development, the vasculature is among the first organs to form and is in charge of maintaining metabolic homeostasis by supplying oxygen and nutrients and removing waste products. As one would expect, blood vessels are critical not only for organ growth in the embryo but also for repair of wounded tissue in the adult. An imbalance in angiogenesis (a time-honored term that globally refers to the growth of new blood vessels) contributes to the pathogenesis of numerous malignant, inflammatory, ischemic, infectious, immune, and wound-healing disorders. This review focuses on the central role of the growth of new blood vessels in ischemic and diabetic wound healing and defines the most current nomenclature that describes the neovascularization process in wounds. There are now two well-defined, distinct, yet interrelated processes for the formation of postnatal new blood vessels, angiogenesis, and vasculogenesis. Reviewed are recent new data on vasculogenesis that promise to advance the field of wound healing.

Fig. 1

The murine femoral ligation model. (A) Exposure of femoral neurovascular bundle and (B) Dissection of the femoral vein and nerve away from the artery with selective femoral artery ligation/excision in FVB mouse.

Fig. 2

BMD EPC recruited to wounds. (A). The Model; (B). Delay healing in ischemic wound (IW) vs. Acute healing in non-ischemic wound (NIW); (C). Wound closure rates (N=7 per time point); (D). Quantification of EPC in wounds and underlying muscle showing increased EPC in acutely healing non-ischemic wounds at days 3 and 7; (E–F). Representative wounds at day 3 (EPC are β-Gal + cells seen staining blue); (G) EPC in wound, underlying muscle, adjacent skin, and remote skin at day 3 after wounding. Data and modified figure re-printed with permission from citation No. 14 (Bauer et. al. J Vasc Surg 2006).

Fig. 3

(A) Scatter-plots and histograms for Sca-1/CD34-expressing cells in peripheral blood from an air-exposed, control mouse; a mouse sacrificed 16 hours after exposure to 2.4 ATA O₂ for 90 minutes, and a mouse first injected with the non-specific NOS inhibitor, L-NAME (40 mg/kg), 30 minutes prior to exposure to HBO₂ and killed 16 hours after exposure. Histograms exhibit cells from three quadrants of the scatter diagrams, excluding only those cells in the lower left quadrant. Plots were gated for small lymphocytes and scans obtained by counting 50,000 gated events. (B) Mean elevations of CD34+, Sca-1+ cells in peripheral circulation of mice. Data are mean ± SE for control mice, immediately after exposure to HBO₂ at 2.4 ATA for 90 minutes, at 16 hours post-HBO₂ and in mice first injected with L-NAME prior to HBO₂. The number of miceincluded in each group are indicated by (n) in the columns, *p<0.05 (ANOVA). Data and modified figure re-printed with permission from citation No. 32 (Thom, et. al. Am J Physiol Heart Circ Physiol 2006).

Fig. 4

Colony forming cell (CFC) capacity of monocytes from blood with or without HBO₂ treatment as designated. Mice were sacrificed 16 hr after HBO₂ exposure for 90min. n=5 mice/group, *p<0.05 (ANOVA). Data and modified figure re-printed with permission from citation No. 32 (Thom, et. al. Am J Physiol Heart Circ Physiol 2006).

Fig. 5

Flow cytometry data from one patient before and after the 1st and 10th HBO₂ treatment. Similar results were observed in other patients and in ischemic and diabetic murine models.–