Vascular cell transcriptomic changes to exercise training differ directionally along and between skeletal muscle arteriolar trees

Abstract

EXT-induced arteriolar adaptations in skeletal muscle are heterogeneous because of spatial variations in muscle fiber type composition and fiber recruitment patterns during exercise. The purpose of this report is to summarize a series of experiments conducted to test the hypothesis that changes in vascular gene expression are signaled by alterations in shear stress resulting from increases in blood flow, muscle fiber type composition, and fiber recruitment patterns. We also report results from a follow-up study of Ankrd23, one gene whose expression was changed by EXT. We expected to see differences in magnitude of changes in gene expression along arteriolar trees and between/among arteriolar trees but similar directional changes. However, transcriptional profiles of arterioles/arteries from OLETF rats exposed to END or SIT reveal that EXT does not lead to similar directional changes in the transcriptome among arteriolar trees of different skeletal muscles or along arteriolar trees within a particular muscle. END caused the most changes in gene expression in 2A arterioles of soleus and white gastrocnemius with little to no changes in the FAs. Ingenuity Pathway Analysis across vessels revealed significant changes in gene expression in 18 pathways. EXT increased expression of some genes (Shc1, desert hedgehog protein (Dhh), adenylate cyclase 4 (Adcy4), G protein-binding protein, alpha (Gnat1), and Bcl2l1) in all arterioles examined, but decreased expression of ubiquitin D (Ubd) and cAMP response element modulator (Crem). Many contractile and/or structural protein genes were increased by SIT in the gastrocnemius FA, but the same genes exhibited decreased expression in red gastrocnemius arterioles. Ankrd23 mRNA levels increased with increasing branch order in the gastrocnemius arteriolar tree and were increased 19-fold in gastrocnemius muscle FA by SIT. Follow-up experiments indicate that Ankrd23 mRNA level was increased 14-fold in cannulated gastrocnemius FA when intraluminal pressure was increased from 90 and 180 cm H2O for 4 hours. Also, Ankrd23 mice exhibit limited ability to form collateral arteries following femoral artery occlusion compared to WT mice (angioscore WT=0.18±0.03; Ankrd23 =0.04±0.01). Further research will be required to determine whether Ankrd23 plays an important role in mechanically induced vascular remodeling of the arterial tree in skeletal muscle.

The Acute Effect of Exercise on Arterial Stiffness in Healthy Subjects: A Meta-Analysis

“…Therefore, continuous exercise leads to an adaptive response of the arteries that includes increased vascular density and increased vasodilatory capacity, improving perfusion. This could be due to the adaptation of the endothelium to the interaction between recurrent hemodynamic tensions and the vasodilatory stimuli of exercise [ 65 ].…”

“…The relationship between peripheral PWv and blood pressure could be due to the elasticity of the large arteries, which gradually decreases towards the periphery [ 66 ]. Exercise results in adaptation of the endothelium to the interaction between hemodynamic tensions and vasodilator stimuli [ 65 ].…”

Cardiovascular Effects and Benefits of Exercise

“…During acute exercise, small arteries and pre-capillary arterioles that supply blood to the skeletal muscles must dilate to increase blood flow through the release of vasodilatory signals (e.g., adenosine, lactate, K + , H + , CO 2 ) from active surrounding muscle ( 110 – 112 ). Repeated exercise leads to an adaptive response in skeletal muscle arterioles that includes increased vascular density coupled with greater vasodilatory capacity, such that enhanced perfusion can occur after conditioning ( 113 – 116 ). This may be partly due to adaptation of the endothelium to the complex interplay of recurrent variations in hemodynamic stresses and vasodilatory stimuli of exercise.…”

Obesity, insulin resistance, and microvascular adaptation

“…In the second of these lectures, focused on one of the most important interventions used to combat obesity and impaired glycemic control in afflicted subjects, Dr. M. Harold Laughlin from the University of Missouri presented “Vascular Cell Transcriptomic Changes To Exercise Training Differ Directionally Along And Between Skeletal Muscle Arteriolar Trees” . In this lecture, Dr. Laughlin describes how chronic exercise training results in shifts in vascular gene expression that were primarily a reflection of the alterations to shear stress, blood flow, muscle fiber type composition, and muscle fiber recruitment patterns.…”