*1.3. Protective Activity of Polyphenols*

Natural polyphenols are a heterogeneous group of secondary metabolites produced in plants that have several functions in the plant kingdom, such as the protection against pathogens, including microorganisms, insects and fungi, and protective activity against ultraviolet radiation and harmful environmental factors; moreover, they can also act as attractants of beneficial organisms [35,36]. These secondary compounds are biosynthesized through the shikimic acid and phenylpropanoid pathways and are believed to be participative in adapting plants in a stressed situation due to environmental changes [37]. These compounds, according to their chemical structures, are divided into various subclasses, such as phenolic acids, flavonoids, tannins, coumarins, lignans, quinones, stilbenes and curcuminoids [38].

New research on plant-derived polyphenols as a guide for exploring innovative synthetic compounds can provide new knowledge to develop new drugs in PAD treatment. In terms of this point, plant-derived natural products approved for therapeutic use in the last 30 years are used for the treatment of various diseases and modulate a wide range of molecular targets. Recent products approved as drugs by the FDA are Veregen® (sinecatechins; green tea (*Camellia sinensis* L.) leaf extract), Fulyzaq® (crofelemer; extract from the red latex of *Croton lechleri* Müll. Arg.) and Grastek® (Timothy grass (*Phleum pratense* L.) pollen allergen extract). Therefore, natural products still represent an important pool for the identification of new pharmacological tools at present.

The purpose of this review is to summarize existing evidence from preclinical and clinical studies on the contribution of natural polyphenols as vasodilators and, in general, as favorable agents for blood circulation, suggesting their potential use in PAD and against an associated causative disease: diabetes. Obviously, vasodilators can be useful not only in PAD, but also in several other cardiovascular diseases, such as hypertension, angina pectoris, heart failure and others. When searching PubMed for "natural polyphenols and vasodilators" or "natural polyphenols and vasodilation" using the criteria "English language" and "full texts", a total of 273 entries were found (23 September 2022), suggesting a wide research interest in the topic (Figure S1). However, when the including criterion "clinical trial" was applied, only six articles remained, of which five referred to the administration in healthy subjects of plant extracts, i.e., grape seed extract [39], apple extract [40], cocoa powder [41], a mixture of three plants (*Kaempferia parviflora*, *Punica granatum* and *Moringa oleifera*) [42] and a beverage containing numerous fruits and vegetables [43]. Only one trial focused on the administration of a single compound, resveratrol, administered in patients after myocardial infarction [44]. Furthermore, another search for "peripheral artery disease and natural compounds" produced only 35 items in the time interval from 1962 up to July 2022 (Figure S2). From these findings, several polyphenolic compounds have been selected and studied in detail in this review. We also wanted to highlight some observations on the importance of physical exercise, as a non-pharmacological approach, in preventing and slowing the onset of circulatory problems, partly derived from a sedentary lifestyle.
