Mice Erections Enabled by Fine-Tuned Penile Blood Flow

A new study in mice provides insights that could one day open therapeutic alternatives for the treatment of erectile dysfunction in humans. For men, sexual health and well-being largely depend on the ability to attain penile erections, which can be compromised by aging and other health risk factors, including diabetes and atherosclerosis. Penile erection is controlled in part by the corpora cavernosa (CC) – erectile vascular tissue that can fill with blood and enlarge upon vasodilation. Sympathetic release of the vasoconstrictor norepinephrine suppresses penile blood flow to a basal level. Upon sexual arousal, nitric oxide and acetylcholine are released, counteracting this effect and resulting in vasodilation within the CC. Although the establishment and maintenance of penile erection is mediated by the balance between these vasodilators and the vasoconstrictor norepinephrine, the regulation of this system isn't fully understood. Eduardo Linck Guimaraes and colleagues investigated the role fibroblasts play in erection physiology. Using single-cell RNA sequencing, optical tissue clearing, and optogenetic activation in a transgenic mouse model, Linck Guimaraes et al. identified two large populations of previously undescribed perivascular fibroblast cells throughout the CC that express the norepinephrine transporter solute carrier family 1, member 3 (SLC1A3). According to the findings, these penile fibroblasts mediate vasodilation of the CC by reducing norepinephrine availability. Moreover, the authors show that the number of fibroblasts in the CC can fine-tune blood flow regulation; increased erection frequency stimulates CC fibroblast proliferation by down-regulating Notch signaling, which results in a higher number of fibroblasts, elevated basal penile blood flow, and reduced norepinephrine sensitivity. Thus, Notch signaling in CC fibroblasts has a dynamic coordinating role in the erectile process. "Although Linck Guimaraes et al. did not examine humans, their study reveals a new therapeutic paradigm of creating conditions that increase norepinephrine uptake or decrease Notch signaling in penile perivascular fibroblasts, which has the potential for translation to treating erectile dysfunction in patients who are unresponsive to [current therapies]," write Ji-Kan Ryu and Gou Young Koh in a related Perspective.