Brendan Olson

Background: Raynaud’s Phenomenon is a disease characterized by aberrant constriction of arterioles in response to various stimuli, typically cold exposure, that is commonly experienced in extremities and other more difficult-to-perfuse areas in the body. Primary Raynaud’s Phenomenon (PRP) has no underlying cause, contrasted with Secondary RP which has similar symptoms but is accompanied by another disease, typically scleroderma.¹ PRP affects approximately 5% of the world’s population with high prevalence in females^2,3 and a significant single nucleotide polymorphism found in the NOS1 gene.⁴ Additionally, the α_2C-adrenoreceptor (α_2C-AR) present in vascular smooth muscle (VSM) has been determined as the primary causative factor in this disease, leading to excessive vasoconstriction in response to cold environments.⁵ A better understanding of the α_2C-AR, not only in VSM but elsewhere throughout the human body, may allow for novel therapeutic targets for PRP.

Objective: In this narrative review, potential therapeutic targets for PRP are discussed along with the associated difficulties in further pursuits to find effective treatments for patients who suffer from PRP.

Search Methods: A PubMed database search was conducted, selecting articles published from 2018-2024 using the “Raynaud Disease” MeSH term along with “Drug Therapy” and “Physiopathology” subheadings. Supplemental articles published before 2018 were selected for background information on PRP.

Results: α_2C-AR gene transcription has been identified to use the cAMP/EPAC/JNK/AP1 pathway within VSM cells.⁶ Additionally, this pathway is associated with  G-Protein Coupled Estrogen Receptor (GPER) on the surface of VSM cells, which has long been hypothesized as one of the reasons for the increased female prevalence of PRP.⁷ Within the cell, trafficking of the α_2C-AR from the endoplasmic reticulum and Golgi compartment to the cell surface is dependent on the interactions of the actin protein Filamin-2 and the carboxyl terminus of the α_2C-AR protein.⁸ Carboxyl terminal decoy peptides have been shown to decrease α_2C-AR expression on the surface of VSM cells in vitro. Manipulating this pathway or the GPER/cAMP/EPAC/JNK/AP1 signaling pathway could be a novel therapeutic strategy for treating PRP. However, difficulties in developing these therapies arise due to the lack of proper animal models to mimic PRP symptoms and pathophysiology. Moreover, the α_2C-AR is abundantly expressed throughout the body (e.g., neurons, fibroblasts, and endocrine cells) and commonly associated with the inhibition of pre-synaptic norepinephrine release.⁹ Administration of direct α_2C-AR antagonists is expected to elicit widespread impacts throughout the body, particularly tachycardia and hypertension. Nevertheless, a recent safety and efficacy trial for a selective α_2C-AR antagonist used for diabetic foot ulcer treatment was shown to be less prone to crossing the blood-brain barrier.¹⁰ It is possible that a similar or modified drug in manipulating α_2C-AR signaling could be the key to prophylactic treatment or reduction of PRP severity.

Conclusions: With the α_2C-AR signaling and trafficking pathways identified, therapeutics that selectively target these involved molecules may soon prove successful in the clinic. Though gaps in knowledge still exist, an animal model with selectively altered transcription of the α_2C-AR gene in VSM may help further investigation and development of effective therapies for PRP.

Works Cited:

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2. Garner R, Kumari R, Lanyon P, Doherty M, Zhang W. Prevalence, risk factors and associations of primary Raynaud’s phenomenon: systematic review and meta-analysis of observational studies. BMJ Open. 2015;5(3):e006389. doi:10.1136/bmjopen-2014-006389
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