Molecular Mechanisms Associated with ROS-Dependent Angiogenesis in Lower Extremity Artery Disease

Abstract

Currently, atherosclerosis, which affects the vascular bed of all vital organs and tissues, is considered as a leading cause of death. Most commonly, atherosclerosis involves coronary and peripheral arteries, which results in acute (e.g., myocardial infarction, lower extremities ischemia) or chronic (persistent ischemia leading to severe heart failure) consequences. All of them have a marked unfavorable impact on the quality of life and are associated with increased mortality and morbidity in human populations. Lower extremity artery disease (LEAD, also defined as peripheral artery disease, PAD) refers to atherosclerotic occlusive disease of the lower extremities, where partial or complete obstruction of peripheral arteries is observed. Decreased perfusion can result in ischemic pain, non-healing wounds, and ischemic ulcers, and significantly reduce the quality of life. However, the progressive atherosclerotic changes cause stimulation of tissue response processes, like vessel wall remodeling and neovascularization. These mechanisms of adapting the vascular network to pathological conditions seem to play a key role in reducing the impact of the changes limiting the flow of blood. Neovascularization as a response to ischemia induces sprouting and expansion of the endothelium to repair and grow the vessels of the circulatory system. Neovascularization consists of three different biological processes: vasculogenesis, angiogenesis, and arteriogenesis. Both molecular and environmental factors that may affect the process of development and growth of blood vessels were analyzed. Particular attention was paid to the changes taking place during LEAD. It is important to consider the molecular mechanisms underpinning vessel growth. These mechanisms will also be examined in the context of diseases commonly affecting blood vessel function, or those treatable in part by manipulation of angiogenesis. Furthermore, it may be possible to induce the process of blood vessel development and growth to treat peripheral vascular disease and wound healing. Reactive oxygen species (ROS) play an important role in regulation of essential cellular signaling pathways such as cell differentiation, proliferation, migration and apoptosis. With regard to the repair processes taking place during diseases such as LEAD, prospective therapeutic methods have been described that could significantly improve the treatment of vessel diseases in the future. Summarizing, regenerative medicine holds the potential to transform the therapeutic methods in heart and vessel diseases treatment.

Keywords: angiogenesis; atherosclerosis; neovascularization; peripheral arterial diseases.

Figure 1

The main risk factors for the progression of peripheral artery disease (PAD)/lower extremity artery disease (LEAD) and mechanisms of pathophysiological impairment associated with PAD. Created with BioRender.

Figure 2

The regulation of hypoxia-inducible factor 1α (HIF-1α) activity. (A) Under normoxic conditions, prolyl hydroxylase (PHD), in the presence of Fe²⁺ and an oxygen molecule, hydroxylates proline residues in the oxygen-dependent degradation domain of HIF-1α. This allows recognition and interaction with the von Hippel-Lindau (pVHL) E3 ubiquitin ligase leading to HIF-1α ubiquitination and subsequent degradation by 26S-proteasome. (B) Under hypoxic conditions, the hydroxylation and degradation of HIF-1α are blocked. Thus, HIF-1α can dimerize with HIF-1β, enter the nucleus and bind hypoxia response elements (HREs) within the promoters of target genes. Together with the co-activator proteins p300 and CBP, the HIF complex transcriptionally regulates the expression of its target genes such as VEGF, PDGF and ANGP, finally regulating many processes including angiogenesis. Created with BioRender.

Figure 3

Neutrophils and monocytes/macrophages in peripheral artery disease (PAD). Neutrophils enhance the activation of monocytes via toll-like receptors (TLRs). TLRs are pattern recognition proteins, and their agonism leads to multiple important cellular mechanisms, like the generation of endoplasmic reticulum stress-ROS, and impairment of endothelial cell repair. Neutrophils potentiate TLR ligation leading to endothelial cell detachment and plaque erosion. Another mechanism indicating the role of neutrophils and monocytes/macrophages in oxidative stress shows that triggering receptors expressed on myeloid cells-1 (TREM-1), as an example of an inflammation marker, participate in the stimulation of these cells via interaction of TREM-ligand with TREM-1, which leads to an increased production of reactive oxygen species (ROS). Created with BioRender.

Figure 4

Neovascularization during LEAD. Angiogenesis, described as the process of new capillary formation from pre-existing capillary beds, and arteriogenesis, the process of vessel dilation and remodeling, can be distinguished during LEAD. The most important molecular factors described in this article that can stimulate or inhibit the neovascularization process are presented. Created with BioRender.