We appreciate the thoughtful commentary provided by Drs Leonidas Karapanos and Ahmet Tevfik Albayrak regarding our recent publication, “A novel rat model for investigating erectile function (EF) after nerve-sparing radical prostatectomy” [1, 2]. As highlighted in their commentary and supported by existing literature, erectile dysfunction (ED) after radical prostatectomy (RP) represents a significant clinical challenge that profoundly impacts patient quality of life [3]. In our study, we meticulously developed and characterized a rat model of nerve-sparing radical prostatectomy (NSRP), with particular emphasis on establishing standardized surgical protocols that closely parallel the anatomical and procedural considerations of human NSRP. This novel rat model was designed to facilitate mechanistic and therapy effect investigations of EF post-NSRP as the preclinical animal model.

A comprehensive understanding of the pathophysiological mechanisms underlying post-RP ED is essential for optimizing surgical decision-making regarding neurovascular bundle (NVB) and related tissues preservation during RP and guiding post-RP interventions. Current evidence strongly implicates iatrogenic NVB injury as the predominant etiological factor contributing to post-RP ED. Consequently, advancements in prostatic surgical anatomy have driven the evolution of various NSRP techniques, all aimed at reducing the incidence of postoperative ED and urinary incontinence [4]. Nevertheless, these refinements, reported rates of post-NSRP ED remain substantial, ranging from 10 to 46% at 1 year and from 6 to 37% at 2 years postoperatively [5]; this is likely related to the patient’s selection and the extent of NVB preservation achieved depending on the surgical skills and methods. Animal models play a vital role in both fundamental mechanistic investigations and preclinical therapeutic research. Quinlan et al. introduced the first Sprague-Dawley rats as the model for investigating EF, supplanting other larger animals [6]. The rat model has since been further developed and optimized. Currently, bilateral cavernous nerve injury (CNI) in rats is widely recognized as the standard experimental model for studying post-RP ED [7]. Many preclinical therapeutic approaches have been developed based on bilateral CNI of rats previously [8]; however, clinical translation of these finding remains limited, and an optimal treatment protocol to facilitate the recovery of EF post-RP has yet to be established [9]. Given these considerations, further research is warranted to elucidate the mechanisms underlying post-RP ED, which may inform the development of more effective therapeutic approaches.

During NSRP, precise identification and reservation of the NVBs remain technically challenging. Recently studies have demonstrated that the extent of periprostatic preservation directly correlates with postoperative EF retention [4]. This observation may be attributed, in part, to the presence of ancillary penile nerves — additional autonomic fibers originating from the major pelvic ganglion (MPG) that supplement the cavernous nerve (CN) in penile innervation. Notably, these ancillary nerves contribute approximately 45% of the intracavernous pressure (ICP) response elicited by electrical stimulation of the medial preoptic area [10]. In the novel rat model, the ancillary penile nerves could be resected while preserving the MPG and CN. This approach minimizes confounding effects from ancillary nerve contributions, thereby enabling more precise investigation of CNI and potential therapeutic interventions for CN regeneration and EF recovery [1].

The pathogenesis of ED following RP is multifactorial, involving direct CNI, compromised penile arterial perfusion, hypoxia-induced cavernosal fibrosis, and neuropraxia-mediated veno-occlusive dysfunction — either independently or synergistically [11]. The novel rat model may encompass a broad spectrum of related factors of NSRP, incorporating both systemic and localized pathophysiological processes, such as hemorrhage, crushing, inflammation, and other adverse events associated with RP, which can collectively impair neuroregenerative processes and delay the recovery of EF following NSRP.

In our study, longitudinal assessment of EF via intracavernosal pressure to mean arterial pressure (ICP/MAP) ratios in following NSRP revealed a significant decline in EF at 1 week postoperatively, followed by substantial recovery by 2 weeks, with ICP/MAP values ultimately approximating those of sham-operated controls. Notably, while smooth muscle content exhibited progressive restoration by 2 weeks, it remained below baseline control levels. The interval between postoperative weeks 1 and 2 appears to represent a critical phase of accelerated functional recovery. However, as Karapanos and Albayrak have emphasized, incorporating a 4-week endpoint could further strengthen the translational validity of this model, particularly given that most prior studies evaluating EF after CNI employ this time point [12].

One limitation of this study was the use of 12-week-old rats, which corresponds to human adolescence. While aged rat models — particularly those with age-related comorbidities as hypertension and diabetes mellitus- may better replicate the clinical context of post-RP ED, their utilization presents practical challenges, including increased procurement costs, anesthetic management complexities, and heightened perioperative care requirements.

This rat model may have some difficulty for scientists or surgeons lacking microsurgical training and experience of rats’ anatomy, potentially limiting its widespread adoption. These barriers can be mitigated through structured training programs, standardized surgical protocols, and collaborative knowledge exchange. By fostering such educational and technical support, the model’s accessibility and reproducibility can be significantly improved, promoting its broader utilization in future studies. We welcome opportunities to share this methodology with interested investigators to collectively advance research in this field.