Krüppel-Like Factor 5 Inhibition Rescues Cavernous Nerve-Injured Erectile Dysfunction by Preventing Phenotypic Switch and Mitochondrial Dysfunction-Dependent Apoptosis in Corpus Cavernosum Smooth Muscle Cells.

Phenotypic switch and apoptosis of corpus cavernosum smooth muscle cells (CCSMCs) contribute to cavernous nerve injury (CNI)-induced erectile dysfunction (CNI-ED). Krüppel-like factor 5 (KLF5) has been identified as a regulator of smooth muscle cell phenotype and apoptosis. Nevertheless, its function in CNI-ED remains unclarified. This work sought to investigate the involvement of KLF5 in a CNI-ED rat model. Fifteen male rats were randomized into sham, unilateral CNI, and bilateral CNI (BCNI) groups to evaluate KLF5 expression. An additional 20 male rats were randomly allocated to the following groups: sham, phosphate-buffered saline-treated BCNI, lentivirus-containing negative control shRNA-treated BCNI, and lentivirus-shRNA targeting Klf5-treated BCNI. Corresponding intracavernous injections were administered immediately after BCNI. Erectile function and histologic changes were assessed 3 weeks later. Additionally, the involvement of KLF5 in the phenotypic switch and apoptosis of hypoxic CCSMCs was investigated. CNI rats exhibited diminished erection, increased hypoxia-inducible factor-1α, KLF5, osteopontin, corporal fibrosis, and apoptosis levels, along with decreased α-smooth muscle actin expression. The severity of these alterations positively correlated with the degree of CNI. Notably, Klf5 inhibition alleviated BCNI-induced ED and corporal damage, and mitigated hypoxia-induced phenotypic switching, oxidative stress, mitochondrial dysfunction, and apoptosis in CCSMCs. Conversely, Klf5 overexpression aggravated these changes. Overall, Klf5 inhibition may prevent BCNI-induced ED and corporal alterations by suppressing phenotypic switch and mitochondrial dysfunction-dependent apoptosis in CCSMCs.