Chronic limb ischemia (CLTI) is the end stage of peripheral arterial disease (PAD). It is a disease characterized by intermittent claudication, ulceration or gangrene of the limbs due to various reasons such as narrowing or occlusion of the arteries and inadequate blood perfusion (Farber, 2018; Beard, 2000). It is a problem with high morbidity and high healthcare costs worldwide. Of these, lower limb ischemic disease is the most common type (Levin et al., 2020). Currently, there is no standardized treatment for CLTI in most countries, and treatment varies considerably from region to region, resulting in CLTI still being associated with higher rates of amputation. Surgical bypass and endovascular therapy are the main blood supply reconstruction strategies for the treatment of CLTI (Cheng and Farber, 2024; Zeller et al., 2009). However, conservative treatments are more in line with the needs of some patients due to the limitations of operators, patients’ arterial disease patterns, surgical risks, available autologous venous bypass access, and patient preferences, placing new demands on the search for appropriate drugs (Desai et al., 2024).
Cathelicidin, a family of antimicrobial peptides (AMPs), is a critical component of the body’s innate immune system and is widely expressed across species. These small bioactive polypeptides are induced in response to infection and inflammation (Agier et al., 2015; Zhang Q. et al., 2023). In humans, cathelicidins are primarily represented by two major groups: defensins and the sole cathelicidin-derived peptide, LL37 (Fry, 2018; Izadpanah and Gallo, 2005). The name “LL37” reflects its structure—a 37-amino acid peptide originating from the N-terminal cleavage of the cathelicidin precursor protein, with leucine (L) as its first two residues.
LL37 exhibits broad-spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria, fungi, and viruses (Luo et al., 2019; Rashki et al., 2022). I Beyond its direct microbicidal effects, LL37 plays a multifaceted role in immune regulation, including modulation of inflammatory mediators, immune cell chemotaxis, cytokine release, endotoxin neutralization, and even tumor suppression or promotion depending on the context (Chieosilapatham et al., 2018; Frasca and Lande, 2012).
The formation of new blood vessels is a prerequisite for tissue repair and improvement of ischemic symptoms (Veith et al., 2019). Angiogenesis is caused by various factors, from mechanical stress and hypoxia to the presence of soluble inflammatory mediators, and involves the germination of small capillaries (angiogenesis) and the growth of existing blood vessels (arteriogenesis) (Eelen et al., 2020; Kuwano et al., 2001). Emerging evidence highlights LL37 as a potent modulator of vascular growth. Studies have shown that LL37 promotes endothelial cell migration, tube formation, and VEGF-mediated signaling, accelerating wound healing and ischemic tissue recovery (Khung et al., 2015). For instance, LL37 activates formyl peptide receptor 2 (FPR2) and Epidermal Growth Factor Receptor/Extracellular Signal-Regulated Kinase (EGFR/ERK) pathways, mimicking pro-angiogenic factors like Vascular Endothelial Growth Factor (VEGF) (Tjabringa et al., 2003; Zhang H. et al., 2023). Additionally, LL37 synergizes with hypoxia-inducible factors (HIFs) to enhance perfusion in diabetic and ischemic models (Rodríguez-Martínez et al., 2008).
Despite these advances, the precise mechanisms by which LL37 influences functional angiogenesis and arterial growth remain incompletely understood. In this study, we investigate the role of LL37 in driving therapeutically relevant angiogenesis and evaluate its potential for treating ischemic diseases.
Leave a Reply