Mechanisms underlying priapism in sickle cell disease: targeting and key innovations on the preclinical landscape.

: Priapism is prolonged penile erection in the absence of sexual arousal or desire and is a devastating condition affecting millions of patients with sickle cell disease (SCD) globally. Available drug treatments for SCD-related priapism remain limited and have been primarily reactive rather than preventive. Hence, there is an unmet need for new drug targets and pharmacologic therapies.: We examine the molecular mechanisms underlying SCD-associated priapism evaluated mostly in animal models. In mouse models of SCD, molecular defects of priapism operating at the cavernous tissue level include reduced tonic NO/cGMP signaling, elevated oxidative/nitrosative stress, vascular adhesion molecule derangements, excessive adenosine and opiorphin signaling, dysregulated vasoconstrictive RhoA/ROCK signaling, and testosterone deficiency. We discuss the consequences of downregulated cGMP-dependent phosphodiesterase type 5 (PDE5) activity in response to these molecular signaling derangements, as the main effector mechanism causing unrestrained cavernous tissue relaxation that results in priapism.: Basic science studies are crucial for understanding the underlying pathophysiology of SCD-associated priapism. Understanding the molecular mechanisms could unearth new therapeutic targets for this condition based on these mechanisms. Treatment options should aim to improve deranged erection physiology regulatory signaling to prevent priapism and potentially restore or preserve erectile function.