Radiotherapy reduces ATP-mediated relaxation in human rectal smooth muscle

Radiation therapy for rectal cancer often causes long-term bowel dysfunction. We investigated radiation-associated motility changes in human rectal smooth muscle, focusing on the role of platelet-derived growth factor receptor alpha-positive (PDGFRα⁺) cells and interstitial cells of Cajal (ICC). Human rectal tissues were obtained from patients undergoing surgery with (n = 61) or without (n = 51) preoperative concurrent chemoradiotherapy (CCRT). Isometric tension recordings were used to assess myogenic responses to potassium chloride (KCl), acetylcholine (ACh), sodium nitroprusside (SNP), and adenosine triphosphate (ATP). Neurogenic components were assessed using electrical field stimulation. Intracellular microelectrode recordings measured slow wave activity. Expression of interstitial cells, neuronal cells, and smooth muscle cells was assessed by immunohistochemistry and quantitative polymerase chain reaction (PCR). ATP-induced relaxation and ATP-associated suppression of slow wave activity were significantly attenuated in irradiated rectal tissue, whereas responses to KCl, ACh, and SNP were preserved. PDGFRA and KIT expression levels were markedly decreased in irradiated tissue (P < 0.001), whereas neuronal nitric oxide synthase 1 (NOS1), vesicular acetylcholine transporter (VAChT), and myosin heavy chain 11 (MYH11) expression levels remained unchanged. Immunostaining confirmed reduced PDGFRα⁺ cells and ICC in irradiated tissue. Pelvic irradiation delivered in the context of preoperative CCRT was associated with reduced PDGFRα⁺ cells and ICC, with associated attenuation of ATP-mediated inhibitory responses, which may contribute to rectal dysmotility. These results suggest that preserving purinergic signaling may offer a potential therapeutic approach to improve long-term bowel function after pelvic radiotherapy.NEW & NOTEWORTHY Pelvic irradiation is associated with attenuated adenosine triphosphate (ATP)-mediated rectal smooth muscle relaxation. The loss of platelet-derived growth factor receptor alpha-positive (PDGFRα⁺) cells is associated with altered rectal neuromodulation. PDGFRα⁺ cells and interstitial cells of Cajal (ICC) are reduced in irradiated rectal tissue. Intrinsic smooth muscle contractile responses are preserved, whereas ATP-mediated inhibitory regulation is reduced.