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Mechanisms of vasodilation to PTH 1–84, PTH 1–34, and PTHrP 1–34 in rat bone resistance arteries

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Abstract

Summary

Parathyroid hormone (PTH) augments bone metabolism and bone mass when given intermittently. Enhanced blood flow is requisite to support high tissue metabolism. The bone arteries are responsive to all three PTH analogs, which may serve to augment skeletal blood flow during intermittent PTH administration.

Introduction

PTH augments bone metabolism. Yet, mechanisms by which PTH regulates bone blood vessels are unknown. We deciphered (1) endothelium-dependent and endothelium-independent vasodilation to PTH 1–84, PTH 1–34, and PTHrP 1–34, (2) the signaling pathways (i.e., endothelial nitric oxide synthase [eNOS], cyclooxygenase [COX], protein kinase C [PKC], and protein kinase A [PKA]), and (3) receptor activation.

Methods

Femoral principal nutrient arteries (PNAs) were given cumulative doses (10−13–10−8 M) of PTH 1–84, PTH 1–34, and PTHrP 1–34 with and without signaling pathway blockade. Vasodilation was also determined following endothelial cell removal (i.e., denudation), PTH 1 receptor (PTH1R) inhibition and to sodium nitroprusside (SNP; a nitric oxide [NO] donor).

Results

Vasodilation was lowest to PTH 1–34, and maximal dilation was highest to PTHrP 1–34. Inhibition of eNOS reduced vasodilation to PTH 1–84 (−80 %), PTH 1–34 (−66 %), and PTHrP 1–34 (−48 %), evidencing the contribution of NO. Vasodilation following denudation was eliminated (PTH 1–84 and PTHrP 1–34) and impaired (PTH 1–34, 17 % of maximum), highlighting the importance of endothelial cells for PTH signaling. Denuded and intact PNAs responded similarly to SNP. Both PKA and PKC inhibition diminished vasodilation in all three analogs to varying degrees. PTH1R blockade reduced vasodilation to 1, 12, and 12 % to PTH 1–84, PTH 1–34, and PTHrP 1–34, respectively.

Conclusions

Vasodilation of femoral PNAs to the PTH analogs occurred via activation of the endothelial cell PTH1R for NO-mediated events. PTH 1–84 and PTHrP 1–34 primarily stimulated PKA signaling, and PTH 1–34 equally stimulated PKA and PKC signaling.

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Acknowledgments

This study was supported by grants from the University of Texas at Arlington Research Enhancement Program and the National Institutes of Arthritis and Musculoskeletal and Skin Diseases (7R15AR062882-02).

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Authors and Affiliations

  1. Department of Kinesiology, University of Texas at Arlington, Arlington, TX, 76019, USA

    T. Benson, T. Menezes & J. Campbell

  2. Bone Vascular and Microcirculation Laboratory, Department of Kinesiology and Applied Physiology, University of Delaware, Newark, DE, 19713, USA

    A. Bice, B. Hood & R. Prisby

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  1. T. Benson
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  2. T. Menezes
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  3. J. Campbell
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Correspondence to R. Prisby.

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The procedures employed in this study were approved by the University of Delaware and University of Texas at Arlington Institutional Animal Care and Use Committees, and conform to the Guide for the Care and Use of Laboratory Animals published by the National Institute of Health (NIH Publication No. 85-23 revised 1996).

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Benson, T., Menezes, T., Campbell, J. et al. Mechanisms of vasodilation to PTH 1–84, PTH 1–34, and PTHrP 1–34 in rat bone resistance arteries. Osteoporos Int 27, 1817–1826 (2016). https://doi.org/10.1007/s00198-015-3460-z

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