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Glycocalyx-targeted therapy ameliorates age-related arterial dysfunction

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Abstract

Advanced age is accompanied by arterial dysfunction, as well as a diminished glycocalyx, which may be linked to reduced high molecular weight–hyaluronan (HMW-HA) synthesis. However, the impact of glycocalyx deterioration in age-related arterial dysfunction is unknown. We sought to determine if manipulations in glycocalyx properties would alter arterial function. Tamoxifen-induced hyaluronan synthase 2 (Has2) reduction was used to decrease glycocalyx properties. Three weeks post-tamoxifen treatment, glycocalyx thickness was lower in Has2 knockout compared to wild-type mice (P<0.05). Has2 reduction induced arterial dysfunction, demonstrated by impaired endothelium-dependent dilation (EDD) and elevated aortic stiffness (P<0.05). To augment glycocalyx properties, old mice received 10 weeks of a glycocalyx-targeted therapy via Endocalyx™ (old+ECX), which contains HMW-HA and other glycocalyx components. Compared to old control mice, glycocalyx properties and EDD were augmented, and aortic stiffness decreased in old+ECX mice (P<0.05). Old+ECX mice had a more youthful aortic phenotype, demonstrated by lower collagen content and higher elastin content than old control mice (P<0.05). Functional outcomes were repeated in old mice that underwent a diet supplemented solely with HMW-HA (old+HA). Compared to old controls, glycocalyx properties and EDD were augmented, and aortic stiffness was lower in old+HA mice (P<0.05). We did not observe any differences between old+HA and old+ECX mice (P>0.05). Has2 reduction phenocopies age-related arterial dysfunction, while 10 weeks of glycocalyx-targeted therapy that restores the glycocalyx also ameliorates age-related arterial dysfunction. These findings suggest that the glycocalyx may be a viable therapeutic target to ameliorate age-related arterial dysfunction.

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Acknowledgements

We thank Dr. Yamaguchi (Sanford-Burnham Medical Research Institute, La Jolla, CA) for providing Has2F/F mice.

Funding

This study was funded in part by grants from the National Institutes of Health (R00 AT010017, R01 AG050238, R01 AG060395, R01 AG048366, K02 AG045339, F31 AG076312) and the Department of Veterans Affairs (I01 BX004492).

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Authors and Affiliations

  1. Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA

    Daniel R. Machin, Daniel W. Trott, Venkateswara R. Gogulamudi, Lisa A. Lesniewski & Anthony J. Donato

  2. Department of Nutrition and Integrative Physiology, Florida State University, Tallahassee, FL, 32306, USA

    Daniel R. Machin

  3. Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA

    Md. Torikul Islam, Samuel I. Bloom, Lisa A. Lesniewski & Anthony J. Donato

  4. Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands

    Hans Vink

  5. MicroVascular Health Solutions LLC, Alpine, UT, USA

    Hans Vink

  6. VA Salt Lake City, GRECC, Salt Lake City, UT, USA

    Lisa A. Lesniewski & Anthony J. Donato

  7. Department of Biochemistry, University of Utah, Salt Lake City, UT, USA

    Anthony J. Donato

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  1. Daniel R. Machin
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Correspondence to Daniel R. Machin.

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HV is Chief Scientific Officer at MicroVascular Health Solutions LLC. DRM, DWT, VRG, MTI, SIB, LAL, and AJD have no conflicts of interest.

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Machin, D.R., Trott, D.W., Gogulamudi, V.R. et al. Glycocalyx-targeted therapy ameliorates age-related arterial dysfunction. GeroScience 45, 2351–2365 (2023). https://doi.org/10.1007/s11357-023-00745-1

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