Current standard pharmacotherapies for underactive bladder (UAB) are cholinergic drugs to stimulate bladder smooth muscle contraction or α1 blockers to reduce lower urinary tract resistance. However, their clinical efficacy remains limited. A previous report indicated the effectiveness of using adipose stem cell sheets in a rat bladder cryoinjury model known as an UAB-like model [1]. A possible mechanism for the effectiveness may be these stem cells-derived growth factors including vascular endothelial growth factor (VEGF), potentially inducing bladder tissue repair [1]. In this study, we investigated the effects of VEGF directly injected into the bladder wall against UAB-like features in a rat bladder cryoinjury model.

Due to most previous reports using female rat model of bladder cryoinjury, we established a male rat model of bladder cryoinjury [2]. Male Wistar rats were divided into four groups: bladder cryoinjured rats administered with vehicle (Injury+V, N=5); bladder cryoinjured rats administered with VEGF (0.1 µg, Injury+VEGF-L, N=4); bladder cryoinjured rats administered with VEGF (1 µg, Injury+VEGF-H, N=5); and rats underwent the surgical procedure without bladder cryoinjury administered with vehicle (Sham+V, N=4). 
Under isoflurane anesthesia, bladder was cryoinjured with dry ice-cooled aluminium rods placed on the bladder wall after filling the bladder with saline (1 ml) through a 30G needle [2]. Sham rats received room-temperature rod application. Three days post-injury, VEGF (0.1 or 1 µg) or saline (200 µl) was injected into the bladder wall under isoflurane anesthesia. Two weeks after the injection, continuous and single cystometry (saline instillation at 4 ml/h) were performed under urethane anesthesia (0.8 g/kg, ip) to evaluate maximal voiding pressure (MVP), voiding pressure (VP), threshold pressure for voiding (TP), intercontraction interval (ICI), bladder capacity (BC), post-void residual urine volume (PVR), and voiding efficiency (VE).

No significant difference was observed in body weight, TP, ICI or BC among the four groups (Table). However, MVP, VP and VE were significantly lower and PVR was significantly higher in the Injury+V group compared with the Sham+V group (Table). On the other hand, the VP decrease in the Injury+V group was significantly reversed in the Injury+VEGF-H group (Table).

Because MVP, VP and VE were significantly reduced in the Injury+V group compared with the Sham+V group, the cryoinjury model in male rats reproduced the functional characteristics of UAB previously observed in female models with cryoinjury [1]. 
We reported that when spontaneously hypertensive rats with chronic bladder ischemia were raised for a long period of more than 56 weeks, these rats developed more severe ischemia in bladder tissue, exhibiting a phenotype similar to that of UAB [3]. Therefore, bladder tissue of UAB may be a condition in which bladder ischemia occurs due to decreased capillary density, making it difficult to maintain the function of peripheral nerves and smooth muscles in the bladder. In this study, local administration of VEGF into the bladder wall partially improved the cryoinjury-induced decrease in VP. Thus, VEGF-mediated local angiogenesis in the bladder can induce bladder blood flow increase, thereby improving UAB-like decrease in bladder contractility without inducing systemic side effects such as cancer cell proliferation.

Local VEGF administration into the bladder wall restored bladder contractile function in a male rat bladder cryoinjury model. Therefore, VEGF-mediated local stimulation of bladder angiogenesis can be a novel therapeutic approach for patients with UAB.

Teraoka S, Honda M, Makishima K, et al. Early effects of adipose-derived stem cell sheets against detrusor underactivity in a rat cryo-injury model. Life Sci. 2022; 301: 120604.
Togo M, Shimizu T, Furihata K, et al. Establishment of a Male Rat Model Exhibiting Myogenic Underactive Bladder-Like Features Following Bladder Cryoinjury. Int J Urol. 2026; 33(1): e70252.
Shimizu S, Nagao Y, Kurabayashi A, et al. Aging-related severe hypertension induces detrusor underactivity in rats. Life Sci. 2021; 283: 119855.