Lack of Tone in Mouse Small Mesenteric Arteries Leads to Outward Remodeling, which can be Prevented by Prolonged Agonist-Induced Vasoconstriction

TY - JOUR

T1 - Lack of Tone in Mouse Small Mesenteric Arteries Leads to Outward Remodeling, which can be Prevented by Prolonged Agonist-Induced Vasoconstriction

AU - Klein, Anika

AU - Joseph, Philomeena D

AU - Christensen, Vibeke Grøsfjeld

AU - Jensen, Lars Jørn

AU - Jacobsen, Jens Christian Brings

N1 - Online accepted manuscript

PY - 2018/9

Y1 - 2018/9

N2 - 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 appears to play a central role. Accordingly, previous data have suggested that an antagonistic and supposedly beneficial response, outward remodeling, may follow prolonged vasodilatation. The present study aimed to determine whether 1) outward remodeling follows 3 days of vessel culture without tone, 2) a similar response can be elicited in a much shorter 4-h timeframe, and, finally, 3) whether a 4-h response can be prevented or reversed by the presence of vasoconstrictors in the medium. Cannulated mouse small mesenteric arteries were organocultured 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 small mesenteric arteries were maintained in physiological saline without tone for 4 h, we detected a similar outward remodeling that proceeded at a rate several times faster. In the 4-h experimental setting, continuous vasoconstriction to ~50% tone by abluminal application of UTP or norepinephrine + neuropeptide Y prevented outward remodeling but did not cause inward remodeling. Computational modeling 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 vascular smooth muscle cell activation induced by prolonged vasoconstrictor exposure. NEW & NOTEWORTHY We have established an effective 4-h 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.

AB - 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 appears to play a central role. Accordingly, previous data have suggested that an antagonistic and supposedly beneficial response, outward remodeling, may follow prolonged vasodilatation. The present study aimed to determine whether 1) outward remodeling follows 3 days of vessel culture without tone, 2) a similar response can be elicited in a much shorter 4-h timeframe, and, finally, 3) whether a 4-h response can be prevented or reversed by the presence of vasoconstrictors in the medium. Cannulated mouse small mesenteric arteries were organocultured 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 small mesenteric arteries were maintained in physiological saline without tone for 4 h, we detected a similar outward remodeling that proceeded at a rate several times faster. In the 4-h experimental setting, continuous vasoconstriction to ~50% tone by abluminal application of UTP or norepinephrine + neuropeptide Y prevented outward remodeling but did not cause inward remodeling. Computational modeling 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 vascular smooth muscle cell activation induced by prolonged vasoconstrictor exposure. NEW & NOTEWORTHY We have established an effective 4-h 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.

U2 - 10.1152/ajpheart.00111.2018

DO - 10.1152/ajpheart.00111.2018

M3 - Journal article

C2 - 29775408

SN - 0363-6135

VL - 315

SP - H644-H657

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

IS - 3

ER -