Engineering vascularized tissues using natural and synthetic small molecules

Abstract

Vascular growth and remodeling are complex processes that depend on the proper spatial and temporal regulation of many different signaling molecules to form functional vascular networks. The ability to understand and regulate these signals is an important clinical need with the potential to treat a wide variety of disease pathologies. Current approaches have focused largely on the delivery of proteins to promote neovascularization of ischemic tissues, most notably VEGF and FGF. Although great progress has been made in this area, results from clinical trials are disappointing and safer and more effective approaches are required. To this end, biological agents used for therapeutic neovascularization must be explored beyond the current well-investigated classes. This review focuses on potential pathways for novel drug discovery, utilizing small molecule approaches to induce and enhance neovascularization. Specifically, four classes of new and existing molecules are discussed, including transcriptional activators, receptor selective agonists and antagonists, natural product-derived small molecules, and novel synthetic small molecules.

Selective Activation of Sphingosine 1-Phosphate Receptors 1 and 3 Promotes Local Microvascular Network Growth

“…The growth and structural enlargement of local microvessels was accompanied by a significant increase in BrdU-positive SMA-stained (SMAþ) cells on the vessel wall, an observation suggestive of pharmacologically induced arteriogenesis. 15,23 Although local sustained release of S1P from PLAGA films allowed for therapeutically relevant concentrations of S1P to be made available to the microvasculature for extended growth, early arteriogenic remodeling was diminished by 7 days postimplantation and the effects of S1P stimulation were no longer statistically significant. In this study, we investigated whether the use of appropriately engineered agonists and antagonists of S1P receptors could be utilized to enhance the results of S1P-induced growth and maintenance of microvascular networks.…”

Engineering in vivo gradients of sphingosine-1-phosphate receptor ligands for localized microvascular remodeling and inflammatory cell positioning

“…Conversely, low activity of intracellular S1P lyase in the blood maintains the plasma concentration of S1P in the low micromolar range [13, 15]. S1P is the endogenous ligand for five known high-affinity G-protein coupled receptors: S1P receptor 1 through 5 (S1P 1–5 ) [16]. Since many circulating cells express one or more of the S1P receptors (S1PRs), the establishment of S1P gradients between the microvasculature and tissue represents a critical determinant of cell trafficking throughout the body [17].…”

Small Molecule Derived From Carboxyethylpyrrole Protein Adducts Promotes Angiogenesis in a Mouse Model of Peripheral Arterial Disease

“…A few existing small molecules have been reported to have angiogenic effects in various assays and animal models 10, 11. Desferoxamine, one of the most established iron chelators, activates HIF‐1 (hypoxia inducible factor 1) and induces high‐level expression of VEGF and erythropoietin mRNA 27, 28.…”

“…Specifically, resveratrol enhanced EPC proliferation, migration, and adhesion and enhanced tube‐like formation by increasing VEGF expression 31. However, resveratrol has opposing effects of being angiogenic at low concentration (2 ng/mL) but inhibiting cell survival and angiogenic pathways at high concentration (1.2 mg/mL) 11. Consequently, it may cause negative effects unless sustained at low dosage.…”

“…Although CEP protein adducts hold promise for developing proangiogenic therapeutics, similar concerns exist as with growth factors in drug development, including batch‐to‐batch variation, high cost of generating recombinant proteins, and a complex process to reach scalable quantities. Alternatively, small molecules might provide a new avenue to discover proangiogenic drugs 10, 11. The advantages of small molecules include that they are chemically stable, easy to modify, and reproducibly manufactured in the cost‐effective manner, and their effects are highly tunable and reversible.…”