Latrophilin-2 is a novel receptor of LRG1 that rescues vascular and neurological abnormalities and restores diabetic erectile function.
Guo Nan YinDo-Kyun KimJi In KangYebin ImDong Sun LeeAh-Reum HanJiyeon OckMin-Ji ChoiMi-Hye KwonAnita LimanjayaSaet-Byel JungJimin YangKwang Wook MinJeongwon YunYongjun KohJong-Eun ParkDaehee HwangJun-Kyu SuhJi-Kan RyuHo Min KimPublished in: Experimental & molecular medicine (2022)
Diabetes mellitus (DM) is a chronic metabolic disorder characterized by inappropriate hyperglycemia, which causes endothelial dysfunction and peripheral neuropathy, ultimately leading to multiple complications. One prevalent complication is diabetic erectile dysfunction (ED), which is more severe and more resistant to treatment than nondiabetic ED. The serum glycoprotein leucine-rich ɑ-2-glycoprotein 1 (LRG1) is a modulator of TGF-β-mediated angiogenesis and has been proposed as a biomarker for a variety of diseases, including DM. Here, we found that the adhesion GPCR latrophilin-2 (LPHN2) is a TGF-β-independent receptor of LRG1. By interacting with LPHN2, LRG1 promotes both angiogenic and neurotrophic processes in mouse tissue explants under hyperglycemic conditions. Preclinical studies in a diabetic ED mouse model showed that LRG1 administration into the penile tissue, which exhibits significantly increased LPHN2 expression, fully restores erectile function by rescuing vascular and neurological abnormalities. Further investigations revealed that PI3K, AKT, and NF-κB p65 constitute the key intracellular signaling pathway of the LRG1/LPHN2 axis, providing important mechanistic insights into LRG1-mediated angiogenesis and nerve regeneration in DM. Our findings suggest that LRG1 can be a potential new therapeutic option for treating aberrant peripheral blood vessels and neuropathy associated with diabetic complications, such as diabetic ED.
Keyphrases
- wound healing
- pi k akt
- signaling pathway
- emergency department
- type diabetes
- mouse model
- peripheral blood
- endothelial cells
- glycemic control
- stem cells
- cell proliferation
- prostate cancer
- cell cycle arrest
- early onset
- epithelial mesenchymal transition
- transforming growth factor
- vascular endothelial growth factor
- poor prognosis
- induced apoptosis
- risk factors
- escherichia coli
- adipose tissue
- mesenchymal stem cells
- benign prostatic hyperplasia
- candida albicans
- weight loss
- pseudomonas aeruginosa
- biofilm formation
- insulin resistance
- staphylococcus aureus
- human health
- reactive oxygen species
- brain injury