Clinical Application of Novel Therapies for Coronary Angiogenesis: Overview, Challenges, and Prospects

Abstract

Cardiovascular diseases continue to be the leading cause of death worldwide, with ischemic heart disease as the most significant contributor. Pharmacological and surgical interventions have improved clinical outcomes, but are unable to ameliorate advanced stages of end-heart failure. Successful preclinical studies of new therapeutic modalities aimed at revascularization have shown short lasting to no effects in the clinical practice. This lack of success may be attributed to current challenges in patient selection, endpoint measurements, comorbidities, and delivery systems. Although challenges remain, the field of therapeutic angiogenesis is evolving, as novel strategies and bioengineering approaches emerge to optimize delivery and efficacy. Here, we describe the structure, vascularization, and regulation of the vascular system with particular attention to the endothelium. We proceed to discuss preclinical and clinical findings and present challenges and future prospects in the field.

Keywords: angiogenesis; bioengineering; clinical trials; extracellular vesicles; gene therapy; stem cells.

Figure 1

Structure of the arterial system. The circulatory system is a network of arteries and veins connected by capillaries where oxygen and nutrient exchange occurs. The inner lining of arteries, arterioles, and capillaries is known as the tunica intima, which is composed exclusively of endothelial cells. Arterioles and arteries additionally have a series of elastic and muscular layers.

Figure 2

Mechanisms of vascularization and extracellular matrix remodeling. (A) Vasculogenesis describes the synthesis of de novo vessels and vasculature that occurs during embryonic development and begins with the differentiation and organization of endothelial progenitor cells. Sprouting angiogenesis is stimulated under hypoxic conditions and is characterized by phalanx, stalk, tip cell migration, proliferation, and tube formation. Arteriogenesis is the process by which shear stress signals for smooth muscle cell recruitment to support an existing vessel between arteries; this vessel then muscularizes to become an established artery. (B) An essential process in angiogenesis is extracellular matrix (ECM) remodeling to release growth factor stores from ECM components and promote migration of endothelial cells. A number of cell types contribute to this process in the heart by production of MMPs; their activation is tightly regulated by the plasminogen system and their inhibitors known as tissue inhibitors of metalloproteinases (TIMPs). VEGF, vascular endothelial growth factor; VEGFR2, VEGF receptor 2; FGF2, fibroblast growth factor 2; IGF, insulin growth factor; HGF, hepatocyte growth factor; PDGF, platelet-derived growth factor; TGFβ, transforming growth factor β; TNFα, tumor necrosis factor α; Ang1, angiopoietin 1; Ang2, angiopoietin 2; HIF1α, hypoxia inducible factor 1α; NOS, nitric oxide synthase; MMPs, matrix metalloproteinases; VE-cadherin; vascular endothelial cadherin; MCP1, monocyte chemoattractant protein 1.

Figure 3

Future challenges and prospects in therapeutic angiogenesis. Cardiac remodeling is characterized by widespread maladaptive changes that adversely affect the structure and function of the heart; these events are further exacerbated by underlying comorbidities such as metabolic syndrome. Combination therapies have the potential to mediate the widespread changes and enhancing revascularization. Furthermore, bioengineering methods may play a valuable role in controlling the release of signaling factors, improving myocardial targeting, and encapsulating many factors.