Angiogenesis and Cardiovascular Diseases: The Emerging Role of HDACs

Abstract

Cardiovascular diseases (CVD) continue to be the leading cause of death in the world despite recent therapeutic advances. Although many CVDs remain incurable, enormous eforts have been placed in harnessing angiogenesis as therapeutics for these diseases. Epigenetics, the modiication of gene expression post-transcriptionally and post-translationally, are important in regulating many biological processes. One of the main post-translational epigenetic modiications, modiication of chromatin structure by the acetylation of histone tails within the chromatin by either histone deacetylases (HDACs) or histone acetyltransferases (HATs), is important in modulating gene transcription and has emerged as an important regulatory player from pathogenesis to therapeutics in CVDs. Particularly, HDACs, which are largely involved in promoting chromatin compaction and hence inhibitions of gene transcription, have been implicated in the pathogenic signalling underlying many aspects of CVDs. Recently, histone modiications have been demonstrated to play important roles in the angiogenesis process. Pharmacological inhibitions of HDACs have displayed promising therapeutic potentials in several pre-clinical models of CVDs where angiogenesis is of paramount importance. There are many evidences proving that pro-and anti-angiogenic therapies-and the impact of epigenetics in these processes-can help to artiicially reconstruct the vasculature in patients with cardiovascular diseases. Conversely, utilising knowledge of HDACs in angiogenesis might help to develop anti-angiogenic therapies in tackling diseases that are characterised with excessive pathological angiogenesis, including cancer and age-related macular degeneration. Understanding the molecular mechanisms underlying HDACs in modulating angiogenesis will undoubtedly beneit future therapeutics development. This chapter focuses on the emerging role of HDACs in angiogenesis and discuss their potentials and challenges in utilising HDAC inhibitors as therapeutics in several major cardiovascular diseases.

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“…Specifically, environmental factors include hypoxia or increased amounts of nitric oxide produced by endothelial cells, which will further stimulate the release of angiogenic triggers. Additionally, mechanical factors, namely hemodynamic and shear stress, have shown to stimulate the development of collateral vessel networks and maintain the patency of newly formed blood vessels [27]. Therefore, the mechanism of angiogenesis is mostly modulated by chemical stimuli, such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), angiopoietins (Ang), hepatocyte growth factor (HGF), hypoxia-inducible factor (HIF), insulin-like growth factor (IGF), transforming growth factor-beta (TGFβ), matrix metalloproteinase (MMP), and tumor necrosis factor (TNF) ( Table 1) [19,22,[27][28][29].…”

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“…During the implementation of the pro‐angiogenic and antiangiogenic therapies, it was noticed that the route of reserving angiogenesis cannot be a therapeutic strategy for treating cardiovascular disease. [ 163 ]…”

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“…The third group are the most diverse subgroup of angiogenesis regulators, comprising both proangiogenic and antiangiogenic proteins, which are responsible for harmonizing different proangiogenic and antiangiogenic signals to either direct angiogenesis forward or halt and reversing the process back 1 . In parallel, mechanical cues, including alterations in tissue hemodynamic and shear stress can induce collateral vascular network formation and stabilize newly developed blood vessels 6 . Finally, The well‐orchestrated interplay between these antiangiogenic and proangiogenic factors is the key element in physiologic progression of angiogenesis process while any shortcomings in each step or molecules will end in aberrant angiogenic responses and development of pathological disorders.…”

“…1 In parallel, mechanical cues, including alterations in tissue hemodynamic and shear stress can induce collateral vascular network formation and stabilize newly developed blood vessels. 6 Finally, The wellorchestrated interplay between these antiangiogenic and proangiogenic factors is the key element in physiologic progression of angiogenesis process while any shortcomings in each step or molecules will end in aberrant angiogenic responses and development of pathological disorders.…”