**8. Concluding remarks and future perspectives**

which was found to promote HIF-1α degradation followed by the downregulation of VEGF expression [92]. There are also reports of the anti-tumoural effects of other HDACi (TSA, sodium butyrate, and VPA) that are also partly mediated by the reduction of VEGFR-2 expres-

SIRT1, a class III HDAC, also plays an important role in tumour initiation, progression, and development of drug resistance by hindering senescence, stress-induced apoptosis [94, 95], and activating cell growth and angiogenesis. MiR-34a, whose expression level was found to be reduced in various tumour cell lines [96, 97], was reported to exert its tumour suppression effect via direct binding onto SIRT1 mRNA and regulate cell apoptosis via SIRT1-p53 pathway [98]. miR-34a also exerts its anti-tumoural effect through inhibiting SIRT1 to induce the senescence

There are emerging HDACi for cancer therapy. HDACi-targeting class I, II, and IV HDACs to be used as anticancer agents are currently under development. One of them, vorinostat, has been approved by FDA for treating cutaneous T-cell lymphoma for patients with persistent or recurrent disease or following two systemic therapies. Other inhibitors, for example, FK228, PXD101, PCI-24781, ITF2357, MGCD0103, MS-275, valproic acid, and LBH589 have also demonstrated therapeutic potential as monotherapy or combination with other anti-tumour drugs [86, 100].

Age-related macular degeneration (AMD) is the leading cause of blindness worldwide. AMD is characterised by the deposition of drusen aggregates under the retinal epithelium. Clusterin is one of the major proteins in drusens [101], and during aging, the expression of clusterin increases [102]. The impact of epigenetic modifications on the pathogenesis of AMD has been reported. It is known that aging affects histone acetylation status, so it is reasonable to presume that the epigenetic regulation might have a role in clusterin expression. It was reported that the treatment with HDACi induces prominent increases in the expression levels of clusterin mRNA and the secretion of clusterin protein. This result indicates that epigenetic factors regulate clusterin expression which could be affecting the pathogenesis of AMD via

Pulmonary arterial hypertension (PAH) is a condition characterised by increased pulmonary vascular resistance and pulmonary artery pressure leading to right heart failure and premature death [104]. During the process, there is a vascular remodelling caused by dysregulated cell proliferation, migration, and survival. The cause of PAH is complex, but the excessive proliferation of SMCs and ECs within the pulmonary artery is thought to play an essential

Elevated levels of HDAC1 and HDAC5 have been observed in the PAH lungs, and treatments with HDACi such as SAHA and VPA reduce disease worsening in rat models of pulmonary hypertension [105]. In addition, MEF2 might have a protective role in PAH progression as the expression of MEF2 and its transcriptional targets are significantly decreased in pulmo-

sion that might be related to repressing tumour angiogenesis [93].

164 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

of EPCs to suppress EPC-mediated tumour angiogenesis [99].

**7.2. Age-related macular degeneration**

**7.3. Pulmonary arterial hypertension**

role in its pathogenesis.

the inhibition of angiogenesis and inflammation [103].

The past 15 years of research have significantly advanced our understanding of the functions and modes of regulation of HDACs in CVD. With all the studies discussed above, we can get an idea about how complex it is to translate HDACi as clinical therapeutics as they exert contradictory functions in many occasions. Extensive evidence for HDAC involvement in multiprotein complexes and cell-specific signalling indicates that a deeper understanding of these pathways will be crucial to effective pharmacological targeting in future.

Although angiogenesis seems to be a very promising therapeutic possibility for the majority of CVDs where patients are not responding to conventional treatments, there are also times that angiogenesis participates in the pathological processes. So in some diseases such as MI and diabetic cardiomyopathy, enhancement of angiogenesis is beneficial by improving recovery of injured myocardium. In the other circumstances where aberrant neoangiogensis is one of the main disease manifestations (such as cancer and AMD), potentiation of anti-angiogenic signalling could be beneficial. Thus, the crucial role that angiogenesis can play as a therapy can only be achieved by thoroughly understanding the underlying mechanisms.

In addition, the diverse and contrasting effects that the current available HDACi exert might be due to their low specificity to a particular HDAC. Class IIa HDACs are expressed in limited organs such as the muscles, brain, or bone, whereas class I HDACs exist ubiquitously. Thus, one may question the specificity and adverse effects of unspecific HDACi for therapeutic uses. Therefore in the future, creation of more specific HDACi, armed with better understanding of the underlying mechanisms of specific HDAC in angiogenesis within each pathological condition, could help the development of more targetted treatments to improve vascularisation and tissue repairs with higher efficiency and efficacy.

Alternative methods where HDAC modulation can be utilised in therapeutic angiogenesis are to modulate endothelial differentiation of stem or progenitor cells, which can be applied as cell therapy to enhance angiogenesis within the ischemic tissues. Next-generation geneediting tool, such as CRISPR-Cas9, can also be extremely useful in accurately targetting specific gene responsible for suppressing or exacerbating angiogenesis depending on the diseases. Moreover, with diseases such as PAH that are characterised by both lack of angiogenesis (within the right ventricles) and excessive angiogenesis (within the pulmonary vasculature), the development of nanoparticles to deliver drugs to specific target tissues can be highly beneficial. This approach will also be extremely useful for patients that manifest both CVD and cancer.

We are currently in an exciting era for translational research with a lot of new inspiring technologies that can truly transform therapeutic approaches. With diligent efforts to devise the role of HDACs underlying angiogenesis robustly in various CVDs, in conjunction with the creation of more selective HDAC inhibitors, advanced engineering solutions, and gene-editing tools to correct genes responsible for repressing angiogenesis, and a commitment in rigorous placebo-controlled clinical trials, superior therapies for CVDs are on the horizon.

## **Author details**

Ana Moraga, Ka Hou Lao and Lingfang Zeng\*

\*Address all correspondence to: lingfang.zeng@kcl.ac.uk

Cardiovascular Division, Faculty of Life Sciences and Medicine, King's College London, London, UK

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eficial. This approach will also be extremely useful for patients that manifest both CVD and

We are currently in an exciting era for translational research with a lot of new inspiring technologies that can truly transform therapeutic approaches. With diligent efforts to devise the role of HDACs underlying angiogenesis robustly in various CVDs, in conjunction with the creation of more selective HDAC inhibitors, advanced engineering solutions, and gene-editing tools to correct genes responsible for repressing angiogenesis, and a commitment in rigor-

Cardiovascular Division, Faculty of Life Sciences and Medicine, King's College London,

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**Provisional chapter**
