Penile cavernous sinusoids are Prox1-positive hybrid vessels

Abstract

Endothelial cells (ECs) of blood and lymphatic vessels have distinct identity markers that define their specialized functions. Recently, specialized hybrid vasculatures with both blood and lymphatic vessel-specific features have been discovered in multiple tissues. Here, we identify the penile cavernous sinusoidal (pc-S) blood vasculature 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 phenotypic alterations related to inflammation response in hybrid ECs in erectile dysfunction. Molecular, ultrastructural and functional studies further establish shared 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.