Therapeutic angiogenesis for treating cardiovascular diseases

Abstract

Cardiovascular disease is the leading cause of death worldwide and is often associated with partial or full occlusion of the blood vessel network in the affected organs. Restoring blood supply is critical for the successful treatment of cardiovascular diseases. Therapeutic angiogenesis provides a valuable tool for treating cardiovascular diseases by stimulating the growth of new blood vessels from pre-existing vessels. In this review, we discuss strategies developed for therapeutic angiogenesis using single or combinations of biological signals, cells and polymeric biomaterials. Compared to direct delivery of growth factors or cells alone, polymeric biomaterials provide a three-dimensional drug-releasing depot that is capable of facilitating temporally and spatially controlled release. Biomimetic signals can also be incorporated into polymeric scaffolds to allow environmentally-responsive or cell-triggered release of biological signals for targeted angiogenesis. Recent progress in exploiting genetically engineered stem cells and endogenous cell homing mechanisms for therapeutic angiogenesis is also discussed.

Keywords: Angiogenesis; Cardiovascular Diseases.

Figure 1

Methods for incorporating biological signals into scaffolds for controlled release. A) Biologics encapsulated directly via physical entrapment. B) Biologics covalently tethered to polymer chains. C) Biologics loaded into microspheres and then encapsulated into hydrogel scaffolds. Reproduced with permission from ref .

Figure 2

A) Polymeric scaffolds for dual delivery of VEGF and PDGF. (B) In vitro release kinetics of VEGF from scaffolds fabricated from PLGA (85:15, lactide:glycolide), measured using 125I-labeled tracers. (C) In vitro release kinetics of PDGF pre-encapsulated in PLGA microspheres (75:25, intrinsic viscosity = 0.69 dl/g; 75:25, intrinsic viscosity = 0.2 dl/g), before scaffold fabrication. D) Dual delivery led to early maturation of blood vessels as demonstrated by α-smooth muscle actin staining at 2 weeks. E) Representative micro-CT images after 5 weeks intramuscular injections of alginate (Blank), alginate containing VEGF165 (VEGF), or alginate containing VEGF165 combined with PLGA microspheres containing PDGF-BB (VEGF/PDGF).(A-D) Reproduced with permission from ref (E) Reproduced with permission from ref .

Figure 3

Effects of VEGF temporal presentation on angiogenesis. Varying amounts of VEGF is applied to human microvascular endothelial cells (HMVEC) over five days in a sprouting assay. Each color bar represents different temporal presentations of VEGF. Red bars represent the same concentration of VEGF applied daily over five days; blue bars represent decreasing VEGF dose over five days; green bars represent gradual decrease in VEGF concentration; and, brown bars represent increasing concentrations of VEGF applied. These are represented in the lower graphs. As shown in the larger graph, decreasing the VEGF dose from an initial high concentraion (blue bars) induced a greater number of endothelial cells sprouts, as compared to constant VEGF doses (50 ng/ml day) (red bars), increasing VEGF doses (brown bars), or a gradual VEGF dose decrease over time (green bars). Reproduced with permission from ref .

Figure 4

Environmental-responsive controlled release system for sustained bFGF delivery in ischemic tissue triggered by pH. TEM micrography of heparinized chitosan/poly(gamma-glutamic acid) (HP-CS/g-PGA) nanoparticles at a distinct pH value: (A) pH 6.0 (after 2 h), (B) pH 7.4 (after 10 min), (C) pH 7.4 (after 30 min), (D) pH 7.4 (after 2 h). (E) Release of bFGF or heparin from the smart nanoparticles, depending on the environmental pH variation. Reproduced with permission from ref .

Figure 5

Cell-triggered VEGF delivery using biomimetic hydrogels. A) Schematic of MMP-degradable PEG hydrogels containing RGD peptide and covalently linked VEGF. B) Cell-triggered VEGF delivery led to targeted angiogenesis within the hydrogel region, whereas soluble VEGF treatment resulted in diffusive and uncontrolled angiogenesis. Reproduced with permission from ref .

Figure 6

Combined stem cell and gene therapy approach for therapeutic angiogenesis (A). Transplantation of genetically modified stem cells into ischemic tissues led to enhanced paracrine secretion and angiogenesis in situ. Reproduced with permission from ref (B). VEGF-overexpressing MSCs using biodegradable polymeric nanoparticles led to enhanced angiogenesis and limb salvage in a murine hindlimb ischemia model (C). Reproduced with permission from ref .

Figure 7

Exploiting cell homing for treating acute myocardial infarction. A) Signaling pathway related to stem cell homing to ischemic tissue. G-CSF promoted cell mobilization and Diprotin A (Dip) inhibited SDF-1 protease, thereby maintaining the stability of cell homing factor SDF-1 released from ischemic tissue. B) G-CSF and Dip dual treatment led to significantly increased myocardial stem cells detected in the ischemic tissue. C) G-CSF and Dip dual treatment increased mouse survival after myocardial infarction. Reproduced with permission from ref .