Penile cavernous sinusoids are Prox1-positive hybrid vessels.

Endothelial cells (ECs) of blood and lymphatic vessels have distinct identity markers that define their specialized functions. Recently, hybrid vasculatures with both blood and lymphatic vessel-specific features have been discovered in multiple tissues. Here, we identify the penile cavernous sinusoidal vessels (pc Ss) as a new hybrid vascular bed expressing key lymphatic EC identity genes Prox1, Vegfr3 and Lyve1. Using single cell transcriptome data of human corpus cavernosum tissue, we found heterogeneity within pc S endothelia and observed distinct transcriptional alterations related to inflammatory processes in hybrid ECs in erectile dysfunction associated with diabetes. Molecular, ultrastructural and functional studies further establish hybrid identity of pc-Ss in mouse, and reveal their morphological adaptations and ability to perform lymphatic-like function in draining high molecular weight tracers. Interestingly, we found that inhibition of the key lymphangiogenic growth factor VEGF-C did not block the development of pc-Ss in mice, distinguishing them from other lymphatic and hybrid vessels analyzed so far. Our findings provide a detailed molecular characterization of hybrid pc-Ss and pave the way for the identification of molecular targets for therapies in conditions of dysregulated penile vasculature, including erectile dysfunction.