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

Abstract

BackgroundCEP (ω‐[2‐carboxyethyl]pyrrole) protein adducts are the end products of lipid oxidation associated with inflammation and have been implicated in the induction of angiogenesis in pathological conditions such as tissue ischemia. We synthesized small molecules derived from CEP protein adducts and evaluated the angiogenic effect of the CEP analog CEP03 in the setting of peripheral arterial disease.Methods and ResultsThe angiogenic effect of CEP03 was assessed by in vitro analysis of primary human microvascular endothelial cell proliferation and tubelike formation in Matrigel (Corning). In the presence of CEP03, proliferation of endothelial cells in vitro increased by 27±18% under hypoxic (1% O2) conditions, reaching similar levels to that of VEGFA (vascular endothelial growth factor A) stimulation (22±10%), relative to the vehicle control treatment. A similar effect of CEP03 was demonstrated in the increased number of tubelike branches in Matrigel, reaching >70% induction in hypoxia, compared with the vehicle control. The therapeutic potential of CEP03 was further evaluated in a mouse model of peripheral arterial disease by quantification of blood perfusion recovery and capillary density. In the ischemic hind limb, treatment of CEP03 encapsulated within Matrigel significantly enhanced blood perfusion by 2‐fold after 14 days compared with those treated with Matrigel alone. Moreover, these results concurred with histological finding that treatment of CEP03 in Matrigel resulted in a significant increase in microvessel density compared with Matrigel alone.ConclusionsOur data suggest that CEP03 has a profound positive effect on angiogenesis and neovessel formation and thus has therapeutic potential for treatment of peripheral arterial disease.

Skeletal Muscle Tissue Engineering: Biomaterials-Based Strategies for the Treatment of Volumetric Muscle Loss

“…They also found significantly higher blood vessel density (CD31 + ) in the defect region in mice treated with FTY720 compared to those treated with a blank scaffold control. Another group also found angiogenic effects with the biomaterial-based delivery of small molecule CEP03, derived from CEP (ω-[2-carboxyethyl]pyrrole) protein adducts [201]. CEP protein adducts are a product of lipid oxidation and accumulate during inflammation and wound healing, but as-is face limitations of protein delivery including high cost and manufacturing challenges.…”

Promoting endogenous repair of skeletal muscle using regenerative biomaterials

“…For example, scaffolds enable localized delivery to the site of injury. Hou et al used a Matrigel plug to deliver CEP03 (a small molecule derivative of (ω‐[2carboxyethyl]pyrrole) protein adducts) to ischemic hind limbs 122 . The CEP03‐releasing Matrigel increased both perfusion and blood vessel density compared to Matrigel alone.…”

Engineering Biomimetic Materials for Skeletal Muscle Repair and Regeneration

“…Although small molecules have been largely studied in vitro or when directly injected in vivo, recent studies are beginning to explore the use of ECM as a delivery system for small molecules. For example, CEP03, a small molecule derivative of (ω‐[2‐carboxyethyl]pyrrole) protein adducts, was injected into ischemic murine muscle when encapsulated within Matrigel, a basement membrane extract derived from Engelbreth–Holm–Swarm (EHS) sarcoma that is rich in ECMs . In comparison to treatment with Matrigel alone, treatment with CEP03‐releasing Matrigel improved blood perfusion recovery to the ischemic muscle by nearly 100%, and increased the capillary density by 6‐fold.…”

“…For example, CEP03, a small molecule derivative of (ω-[2-carboxyethyl]pyrrole) protein adducts, was injected into ischemic murine muscle when encapsulated within Matrigel, a basement membrane extract derived from Engelbreth-Holm-Swarm (EHS) sarcoma that is rich in ECMs. [100] In comparison to treatment with Matrigel alone, treatment with CEP03-releasing Matrigel improved blood perfusion recovery to the ischemic muscle by nearly 100%, and increased the capillary density by 6-fold. As the benefits of delivering small molecules in a supportive biomaterial niche become increasingly apparent, it is likely that scaffold-mediated delivery of therapeutic small molecules will develop into a more widely used approach in the future.…”