Micah Thomas

Background: Peripheral artery disease (PAD) is the manifestation of atherosclerosis with narrowed arterial blood vessels and reduced limb blood flow. This usually affects the lower extremities¹ and leads to a decrease in capillary density and microvascular perfusion.² About 12-20% of people 60+ years old are affected. This increases to 50% of people after the age of 85.¹ About 50% of patients have generalized lower extremity pain that does not get relieved with rest.³ Patients may additionally present with decreased pulses, impaired walking ability, non-healing wounds, and tissue ischemia.³ Therapies designed to promote new vessel growth by angiogenesis and improve blood flow have not been effective. A new mechanistic target to consider may be the regulation of microRNA-126 as it is known to aid in angiogenesis through inhibition of PI3KR2 and Spred-1.

Objective: In this review we will investigate whether peripheral artery disease utilizes the vascular endothelial growth factor (VEGF) angiogenesis pathway, and determine whether this mechanism can be utilized to create a therapeutic tool for patients with PAD.

Search Methods: A literature search using PubMed was conducted from 2018-2024 with the keywords “peripheral artery disease”, “angiogenesis” and “endothelial dysfunction”.

Results: A recent study determined that the damaged endothelial human cells released tissue factor.⁷ This factor showed a direct correlation with microRNA-126 expression.⁷ Endothelial cells with tissue factor silenced also showed decreased microRNA expression.⁷ The expression of microRNA-126 in monocytes led to a decrease in proinflammatory cytokine mRNA levels.⁷ In another study, female mice treated with microRNA performed better functionally than the groups that were not, as determined using a Tarlov score.⁶ It was also evident that mice treated with microRNA-126 showed increased angiogenesis, muscle development in their hind legs, and the highest levels of VEGF at four time points.⁶ These microRNA treated mice had decreased mRNA expression of PI3KR2 and SPRED-1 at all four data collection times.⁶ The microRNA treated mice also had higher microvessel density scores than the placebo group.⁶ Moderate intensity walking increased circulating microRNA-126 levels⁸ and decreased levels of PI3KR2 and Spred-1 inhibitory factors in PAD patients.⁸ Increased levels of VEGF in gastrocnemius muscle biopsies were also noted after exercise.⁸ Additionally, exercise increased walking tolerance and muscle tone of lower extremities in patients with PAD.²

Conclusion: MicroRNA-126 is a key mediator of endothelial damage in ischemic injury events, such as PAD. MicroRNA-126 expression showed a direct correlation with endothelial cell injury, and an indirect correlation with VEGF inhibitory factors PI3KR2 and SPRED-1. Angiogenesis is activated through the VEGF pathway in patients with PAD after increased microRNA-126 expression. Exercise could play a key role in recovery from PAD by serving as a therapeutic tool to stimulate microRNA signaling linked to angiogenesis.

Works Cited:

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2. da Silva ND Jr, Andrade-Lima A, Chehuen MR, et al. Walking Training Increases microRNA-126 Expression and muscle capillarization in patients with peripheral artery disease. Genes (Basel). 2022;14(1):101. Published 2022 Dec 29. doi:10.3390/genes14010101
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