Exercise training causes differential changes in gene expression in diaphragm arteries and 2A arterioles of obese rats

Laughlin, M. Harold; Padilla, Jaume; Jenkins, Nathan T.; Thorne, Pamela K.; Martin, Jeffrey S.; Rector, R. Scott; Akter, Sharmin; Davis, JO

doi:10.1152/japplphysiol.00317.2015

Cited by 10 publications

(21 citation statements)

References 66 publications

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“…A recent series of studies evaluated the effects of regular exercise on the vascular transcriptome in pigs (238) and rats (174,175,235). A common finding is that the effects of exercise are heterogeneous across vascular beds.…”

Section: Changes In Vascular Cell Gene Expression Induced By Exercmentioning

confidence: 99%

Vascular Adaptation to Exercise in Humans: Role of Hemodynamic Stimuli

Green

Hopman

Padilla

et al. 2017

Physiological Reviews

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On the 400 th anniversary of Harvey's Lumleian lectures, this review focusses on the impact of physical exercise on "hemodynamic" forces associated with the movement of blood through arteries in humans and the functional and structural adaptations that result from repeated episodic exposure to such stimuli. The late 20 th century discovery that endothelial cells modify arterial tone via paracrine transduction, provoked studies exploring the direct mechanical effects of blood flow and pressure on vascular function and adaptation in vivo. In this review, we address the impact of distinct hemodynamic signals that occur in response to exercise, the inter-relationships between these signals, the nature of the adaptive responses that manifest under different physiological conditions and the implications for human health.Exercise modifies blood flow, luminal shear stress, arterial pressure and tangential wall stress, all of which can transduce changes in arterial function, diameter and wall thickness.There are important clinical implications of the adaptation that occurs as a consequence of repeated hemodynamic stimulation associated with exercise training in humans, including impacts on atherosclerotic risk in conduit arteries, the control of blood pressure in resistance vessels, oxygen delivery and diffusion, and microvascular health. Exercise training studies have demonstrated that direct hemodynamic impacts on the health of the artery wall contribute substantially to the well-established decrease in cardiovascular risk attributed to physical activity.

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Section: Changes In Vascular Cell Gene Expression Induced By Exercmentioning

confidence: 99%

Vascular Adaptation to Exercise in Humans: Role of Hemodynamic Stimuli

Green

Hopman

Padilla

et al. 2017

Physiological Reviews

Self Cite

530

570

View full text Add to dashboard Cite

show abstract

“…[15][16][17]27 Nevertheless, the notion that the effects of exercise are not the same among skeletal muscle arteries can be reconciled with the understanding that during exercise different muscle fiber recruitment patterns exist among these skeletal muscles, thus likely contributing to this differing vascular effect of training between muscles and even within muscles. 17,27 Perhaps more surprising was our recent finding that obesity, viewed as a condition with systemic complications, also resulted in striking heterogeneous effects among arteries examined. 24,28,29 Indeed, we identified 20 genes whose expression was consistently altered among 15 arteries, which represented only a $9% overlapping effect of obesity among all arteries examined.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic effects of metformin in skeletal muscle arteries of obese insulin-resistant rats

Padilla

Thorne

Martin

et al. 2017

Exp Biol Med (Maywood)

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This study provides evidence that metformin treatment produces artery-specific gene expression effects. The genes whose expression was modulated with metformin do not appear to have a clear connection with its known mechanisms of action. AbstractWe examined the effects of metformin, a commonly used antidiabetic drug, on gene expression in multiple arteries. Specifically, transcriptional profiles of feed arteries and second branch order arterioles in the soleus, gastrocnemius, and diaphragm muscles as well as aortic endothelial scrapes were examined from obese insulin-resistant Otsuka Long-Evans Tokushima Fatty rats treated with (n ¼ 9) or without (n ¼ 10) metformin from 20 to 32 weeks of age. Metformin-treated rats exhibited a reduction in body weight, adiposity, and HbA1c (P < 0.05). The greatest number of differentially expressed genes (FDR < 15%) between those treated with and without metformin was found in the red gastrocnemius 2a arterioles (93 genes), followed by the diaphragm 2a arterioles (62 genes), and soleus 2a arterioles (15 genes). We also found that two genes were differentially expressed in aortic endothelial cells (LETMD1 and HMGCS2, both downregulated), one gene in the gastrocnemius feed artery (BLNK, downregulated), and no genes in the soleus and diaphragm feed arteries and white gastrocnemius 2a arterioles. No single gene was altered by metformin across all vessels examined. This study provides evidence that metformin treatment produces distinct gene expression effects throughout the arterial tree in a rat model of obesity and insulin resistance. Genes whose expression was modulated with metformin do not appear to have a clear connection with its known mechanisms of action. These findings support the notion that vascular gene regulation in response to oral pharmacological therapy, such as metformin, is vessel specific.

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“…The EXT components of the study indicated that both types of EXT caused heterogeneous patterns of altered gene expression within and among the arteriolar trees of these three muscles in T2D (OLETF) rats . For example, SIT training altered expression of 445 genes with differential expression in the diaphragm FA, 171 genes in the SFA, and 16 genes in the gastrocnemius FA, yet there were only two genes that had increased expression in all three FAs .…”

Section: Ext‐induced Adaptations Of Vascular Structure and Function Amentioning

confidence: 95%

“…We used the OLETF rat model to examine the interactive effects of EXT and obesity/T2D on the skeletal muscle arteriolar tree. Importantly, we used arteriolar samples taken from the same animals used for the studies of vasomotor reactivity to determine transcriptional profiles with techniques described previously . The EXT rats had lower body weights and higher heart weight/body weight ratios, lower percent body fat and % HbA1c, and increased citrate synthase activity of the red and white portions of the vastus lateralis muscle.…”

Section: Ext‐induced Adaptations Of Vascular Structure and Function Amentioning

confidence: 99%

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

et al. 2017

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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.

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Exercise training causes differential changes in gene expression in diaphragm arteries and 2A arterioles of obese rats

Cited by 10 publications

References 66 publications

Vascular Adaptation to Exercise in Humans: Role of Hemodynamic Stimuli

Vascular Adaptation to Exercise in Humans: Role of Hemodynamic Stimuli

Transcriptomic effects of metformin in skeletal muscle arteries of obese insulin-resistant rats

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

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