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Effects of intrauterine growth restriction on Ca2+-activated force and contractile protein expression in the mesenteric artery of 1-year-old Wistar-Kyoto rats

Abstract

Intrauterine growth restriction (IUGR) affects vascular reactivity in older rats, but at present the causative factors for this change are unknown. Therefore, we investigated downstream events associated with vascular reactivity, specifically, Ca2+-regulated force production and shifts in contractile protein content. The mesenteric artery from male and female 1-year-old Wistar-Kyoto rats was examined using two distinct experimental growth restriction models. Uterine ligation surgery restriction or a sham surgery was conducted at day 18 of pregnancy, whilst a food restriction diet (40% control diet) began on gestational day 15. Extracellular vascular reactivity was studied using intact mesenteric arteries, which were subsequently chemically permeabilized using 50 μM β-escin to examine Ca2+-activated force. Peak contractile responses to a K+-induced depolarization and phenylephrine were significantly elevated due to an increase in maximum Ca2+-activated force in the male surgery restricted group. No changes in contractile forces were reported between female experimental groups. Sections of mesenteric artery were examined using western blotting, revealing IUGR increased the relative abundance of the voltage-gated Ca2+ channel, inositol-1,4,5-trisphosphate receptor and myosin light chain kinase, in both male growth restricted groups, whereas no changes were seen in females. These findings demonstrate for the first time in 1-year-old rats that changes in vascular reactivity due to IUGR are caused by a change in Ca2+-activated force and shifts in important contractile protein content. These changes affect the Wistar-Kyoto rat in a sex-specific and maternal insult-dependent manner.

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Abbreviations

ACh:

Acetylcholine

C:

Control

CaV1.2:

α1C L-type voltage-gated Ca2+-channel

EGTA:

Ethylene glycol bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acid

FR:

Food restricted

IP3R1:

Inositol trisphosphate receptor 1

IUGR:

Intrauterine growth restriction

MLC:

Myosin light chain

MLCK:

Myosin light chain kinase

MLCP:

Myosin light chain phosphatase

Myh11:

Smooth muscle myosin heavy chain

Mypt1:

Myosin light chain phosphatase target subunit 1

PE:

Phenylephrine

PSS:

Physiological saline solution

SC:

Surgical control

SR:

Surgical restricted

TBST:

Tris buffered saline-Tween

TPM4:

Tropomyosin 4

WKY:

Wistar-Kyoto

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Acknowledgments

The authors would like to thank Maria Cellini, Heidy Flores, and Aida Youssef for technical assistance, and Simon Watson for statistical analysis design.

Funding information

All funding provided by La Trobe University; WBS 4.0062.10.35.

Author information

Correspondence to Michael J. Christie.

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The authors declare that they have no competing interests.

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Key points

• IUGR increased maximum Ca2+-activated force in male resistance arteries

• Concurrent increase in contractile protein expression of male IUGR arteries

• No contractile or biochemical changes in female IUGR mesenteric arteries

• Sex-specific and maternal insult-dependent effect of IUGR on resistance arteries

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Christie, M.J., Romano, T., Murphy, R.M. et al. Effects of intrauterine growth restriction on Ca2+-activated force and contractile protein expression in the mesenteric artery of 1-year-old Wistar-Kyoto rats. J Physiol Biochem (2020). https://doi.org/10.1007/s13105-020-00724-6

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Keywords

  • Ca2+-activated force
  • Contractile proteins
  • Intrauterine growth restriction
  • Resistance arteries
  • Vascular smooth muscle