Peripheral artery disease (PAD) poses a great challenge to society, with a growing prevalence in the upcoming years. Patients in the severe stages of PAD are prone to amputation and death, leading to poor quality of life and a great socioeconomic burden. Furthermore, PAD is one of the major complications of diabetic patients, who have higher risk to develop critical limb ischemia, the most severe manifestation of PAD, and thus have a poor prognosis. Hence, there is an urgent need to develop an effective therapeutic strategy to treat this disease. Therapeutic angiogenesis has raised concerns for more than two decades as a potential strategy for treating PAD, especially in patients without option for surgery-based therapies. Since the discovery of gene-based therapy for therapeutic angiogenesis, several approaches have been developed, including cell-, protein-, and small molecule drug-based therapeutic strategies, some of which have progressed into the clinical trial phase. Despite its promising potential, efforts are still needed to improve the efficacy of this strategy, reduce its cost, and promote its worldwide application. In this review, we highlight the current progress of therapeutic angiogenesis and the issues that need to be overcome prior to its clinical application.

Rhodiola is an ancient wild plant that grows in rock areas in high-altitude mountains with a widespread habitat in Asia, Europe, and America. From empirical belief to research studies, Rhodiola has undergone a long history of discovery, and has been used as traditional medicine in many countries and regions for treating high-altitude sickness, anoxia, resisting stress or fatigue, and for promoting longevity. Salidroside, a phenylpropanoid glycoside, is the main active component found in all species of Rhodiola. Salidroside could enhance cell survival and angiogenesis while suppressing oxidative stress and inflammation, and thereby has been considered a potential compound for treating ischemia and ischemic injury. In this article, we highlight the recent advances in salidroside in treating ischemic diseases, such as cerebral ischemia, ischemic heart disease, liver ischemia, ischemic acute kidney injury and lower limb ischemia. Furthermore, we also discuss the pharmacological functions and underlying molecular mechanisms. To our knowledge, this review is the first one that covers the protective effects of salidroside on different ischemia-related disease.

Although all the mutants' activities decreased, the mutant L197E with the maximum activity retain suggested that the loop structure (residues 194 to 211) may be the favored candidate sites to enhance thermostability. In addition, CA 7α-HSDH may suffer structural destruction resulting from the proline substitution in A104 and G105.

Therapeutic angiogenesis is a potential therapeutic strategy for hind limb ischemia (HLI); however, currently, there are no small-molecule drugs capable of inducing it at the clinical level. Activating the hypoxia-inducible factor-1 (HIF-1) pathway in skeletal muscle induces the secretion of angiogenic factors and thus is an attractive therapeutic angiogenesis strategy. Using salidroside, a natural glycosidic compound as a lead, we performed a structure–activity relationship (SAR) study for developing a more effective and druggable angiogenesis agent. We found a novel glycoside scaffold compound (C-30) with better efficacy than salidroside in enhancing the accumulation of the HIF-1α protein and stimulating the paracrine functions of skeletal muscle cells. This in turn significantly increased the angiogenic potential of vascular endothelial and smooth muscle cells and, subsequently, induced the formation of mature, functional blood vessels in diabetic and nondiabetic HLI mice. Together, this study offers a novel, promising small-molecule-based therapeutic strategy for treating HLI.

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