The Role of Angiogenesis in Coronary Artery Disease: A Double-Edged Sword: Intraplaque Angiogenesis in Physiopathology and Therapeutic Angiogenesis for Treatment

Abstract

Angiogenesis is described as a sprouting and growth process of new blood vessels from pre-existing vasculature. The relationship between angiogenesis and coronary artery disease (CAD) is double-sided. On one hand, angiogenesis within plaques is responsible for facilitating the growth and vulnerability of plaques by causing intraplaque hemorrhage and inflammatory cell influx, and overabundance of erythrocytes and inflammatory cells within a plaque probably causes plaque rupture, further leading to acute coronary syndrome. Therefore, inhibiting intraplaque angiogenesis has been considered as a potential therapeutic target for CAD. On the other hand, aiming at improving reperfusion to the ischemic myocardium in patients with CAD, angiogenesis promoting has been utilized as a therapeutic approach to expand myocardial microvascular network. Current strategies include direct administration of angiogenic growth factors (protein therapy), promoting angiogenic genes expression in vivo (gene therapy), and delivering stem cells (cell therapy) or exosomes (cell free therapy). This article will start by clarifying the basic concept of angiogenesis, interpret the mechanism of excessive intraplaque angiogenesis in atherosclerosis, and discuss its role in the growth and vulnerability of plaques. Then we will focus on the four distinct strategies of therapeutic angiogenesis. Despite promising animal studies and smallscale clinical trials of therapeutic angiogenesis in patients with ischemic heart disease, investigations have far not shown definite evidence of clinical efficacy. Hence, while acknowledging future work that remains to be done to validate the clinical results, we reviewed the critical challenges in this arena and highlighted the exciting progress that has occurred recently.

LncRNA NORAD Promotes Vascular Endothelial Cell Injury and Atherosclerosis Through Suppressing VEGF Gene Transcription via Enhancing H3K9 Deacetylation by Recruiting HDAC6

“…Vascular endothelial growth factor (VEGF) is a recognized growth factor playing pivotal roles in angiogenesis through increasing the proliferation rate and activities of endothelial progenitor cells (EPCs) (Yancopoulos et al, 2000;Jin et al, 2015). Angiogenesis could effectively relieve atherosclerotic diseases including CAD (Camare et al, 2017;Wu et al, 2018;Ma Q. et al, 2020), while endothelial cell injury and endothelial dysfunction impair angiogenesis (Xing et al, 2017;Ungvari et al, 2018). Numerous studies have demonstrated that VEGF could attenuate endothelial cell injury or endothelial dysfunction to relieve the pathogenesis of patients with CAD (Jin et al, 2015;Longchamp et al, 2018;Liang et al, 2020).…”

Tetramethylpyrazine and Paeoniflorin Inhibit Oxidized LDL‐Induced Angiogenesis in Human Umbilical Vein Endothelial Cells via VEGF and Notch Pathways

“…Previous studies have demonstrated that low concentrations of ox-LDL promote angiogenesis in human endothelial cells, thus leading to plaque vulnerability and intravascular thrombosis [7–10]. Therefore, the inhibition of angiogenesis has been considered as a potential therapeutic target in atherosclerosis [11].…”

Holistic Regulation of Angiogenesis with Chinese Herbal Medicines as a New Option for Coronary Artery Disease

“…The relationship between angiogenesis and CAD is double-sided [ 4 ]; balancing the contradictory angiogenesis effects might facilitate drug efficacy in CAD. Chinese herbal medicines have an advantage over regulating the balance of the body in different pathological states.…”

“…Improving blood flow to the ischemic myocardium plays a critical role in the treatment of CAD, and angiogenesis is an important and promising means of increasing blood flow [ 12 ]. Numerous studies have shown that promoting angiogenesis therapy can improve myocardial ischemia by stimulating formation of collateral networks and increasing blood supply [ 4 , 13 ]. Nox4 alleviated hypoxia/reoxygenation injury by inhibiting apoptosis and promoting angiogenesis via upregulation of HIF-1/VEGF signaling pathway [ 14 ].…”

“…However, a large number of patients do not qualify for surgical or interventional procedures [ 3 ], and these patients mainly present with refractory angina with severe atherosclerosis in the clinic. At present, a number of studies have indicated that promoting angiogenesis is a promising approach for IHD [ 4 ], while angiogenesis in atherosclerosis induces plaque destabilization and hemorrhage [ 5 ]. Therefore, more attention should be paid to balancing the regulation of angiogenesis in myocardial ischemia and atherosclerosis.…”