**4. Conclusions**

Polyphenols have been extensively investigated for their beneficial effects on many clinical conditions, as well as cardiovascular-related diseases. Despite the profusion of experimental data suggesting potential mechanisms favorable for clinical use, trials on the side of peripheral vascular diseases are still hindered by the absence of large studies with sufficient statistical power in order to demonstrate the true efficacy of the compounds. The requirement of large resources to program a clinical study that does not necessarily allow for a unique patent outcome often discourages an industrial gamble, reducing the real possibility of developing new drugs in therapy. Resources for research on natural products from non-profit organizations are necessary.

Emerging polyphenolic compounds were selected based on their appearance in the literature and have been discussed here, with a focus on their role in improving endothelial and, in general, vascular functions; molecular mechanisms and preclinical and clinical evidence were highlighted. Overall, the data collected in this review suggest the potential role of selected polyphenols in the treatment of PAD, also concomitant with DM; however, clinical data on efficacy are still limited and need to be improved. Despite the extensive preclinical experimental results that confirm the potential role of baicalein, curcumin, quercetin, mangiferin and resveratrol against vascular diseases, their clinical effectiveness is still only preliminarily demonstrated, although there is evidence of safety for the selected doses. Natural-drug compounds that provide significant biological activities in the specific vascular district have been suggested, and the task of a chemical approach could be directed to optimize their bioavailability. However, caution should be devoted to the fact, as already observed that, for example, with curcumin, an absolute increase in bioavailability does not necessarily mean an improved benefit/risk ratio when the product is introduced for clinical use. Moreover, derivatives or analogs obtained on the structural basis of natural products do not necessarily produce to compounds that are safe for human use. The occurrence in the molecule of phenolic hydroxyl groups also raises the question of biological stability as drugs. Therefore, a new concept of the wise use of available natural resources should be applied, also in the prospective development of drugs, keeping in mind the limits and advantages of medicinal plants and relative natural compounds.

As a general consideration, a diet rich in polyphenols reduces the risk of cardiovascular adverse events, including PAD. Polyphenols, together with adequate moderate aerobic exercise, can help prevent and reverse age-associated arterial stiffness. In fact, exercise therapy is considered a class IA (highest level) recommendation for the treatment of patients with PAD. Unfortunately, the long-term participation in perspective clinical and population-based programs is scarce, and therefore this approach is still just outlined. The use of polyphenols, both as dietary intake and dietary supplements, could represent a favorable approach to maintaining the integrity of peripheral blood vessels and limiting the harmful effect of oxidants. The present evidence suggests the validity of further clinical trials to define the role of this class of compounds in the prevention and treatment of vascular artery disease.


**Table 1.**

Plant-derived

polyphenols

 with potential activity in preventing

 or improving

cardiovascular

 diseases and, thus, also PAD: in vitro



AGEs, advanced glycation end-products; AMPK, adenosine monophosphate-activated protein kinase; CAMs, cell adhesion molecules; GO, glyoxal; HIF–1α, hypoxia-inducible factor 1α; HAECs, human aortic endothelial cells; HRPE cells, human retinal pigment epithelial cells; HUVECs, human umbilical vein endothelial cells; IL–6 or IL–8, interleukin–6 or –8; ICAM–1, intercellular adhesion molecule 1, MCP–1, monocyte chemoattractant protein–1; MGO, methylglyoxal; NOX2, phagocytic NADPH oxidase, NO, nitric oxide; eNOS, endothelial nitric oxide synthase; O2•−, superoxide anion; VSMCs, vascular smooth-muscle cells; dSCA, denuded-sheep coronary arteries; PKC, protein kinase C; RRCECs, rat retinal capillary endothelial cells; SIRT1, silent mating- type information regulation 2 homolog 1.


protein occludin


*Molecules* **2022**, *27*, 7110

**Table 2.**

Plant-derived

 polyphenols

 with potential activity in preventing

cardiovascular

 diseases and, thus, also PAD: clinical trials and adverse

**Supplementary Materials:** The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/molecules27207110/s1, Figure S1: Flowchart showing articles on polyphenols listed in PubMed from 1994 to 23 September 2022; Figure S2: Flowchart showing articles on peripheral artery disease and natural compounds listed in PubMed from 1963 to 23 September 2022.

**Author Contributions:** G.F. and E.R. wrote and revised the text. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.
