Inward remodeling of resistance vessels is an independent risk factor for cardiovascular events. Thus far, the remodeling process remains incompletely elucidated, but the activation level of the vascular smooth muscle cell (VSMC) appears to play a central role. Accordingly, previous data suggest that an antagonistic and, supposedly beneficial, response - outward remodeling - may follow prolonged vasodilatation. This study aims to determine if 1) outward remodeling follows 3 days of vessel culture without tone, 2) a similar response can be elicited in a much shorter 4-hour time frame and finally 3) a 4-hour response can be prevented or reversed by the presence of vasoconstrictors in the medium. Cannulated mouse small mesenteric arteries (SMA) were organo-cultured for 3 days in the absence of tone, leading to outward remodeling that continued throughout the culture period. In more acute experiments in which cannulated SMAs were maintained in physiological saline without tone for 4 hours, we detected a similar outward remodeling that proceeded at a rate several times faster. In the 4-hour experimental setting, continuous vasoconstriction to approximately 50% tone by abluminal application of uridine 5’-triphosphate (UTP) or norepinephrine (NE) + neuropeptide Y (NPY) prevented outward remodeling but did not cause inward remodeling. Computational modelling was used to simulate and interpret these findings and to derive time constants of the remodeling processes. It is suggested that depriving resistance arteries of activation will lead to eutrophic outward remodeling, which can be prevented by VSMC activation induced by prolonged vasoconstrictor exposure.

NEW AND NOTEWORTHY: We have established an effective 4-hour method for studying outward remodeling in pressurized mouse resistance vessels ex vivo and have determined conditions that block the remodeling response. This allows for investigating the subtle but clinically highly relevant phenomenon of outward remodeling while avoiding both laborious 3-day organoid culture of cannulated vessels and in vivo experiments lasting several weeks.