MFAP4-Deficiency Aggravates Age-Induced Changes in Resistance Artery Structure, While Ameliorating Hypertension

Kimmie B Christensen, Şeyda Ünsal, Morten F Ebbesen, Line Hemstra, Anders Schlosser, Kristoffer Rosenstand, Pernille B L Hansen, Boye L Jensen, Maria Bloksgaard, Ulf Simonsen, Grith L Sorensen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

BACKGROUND: Abnormalities of resistance arteries may play essential roles in the pathophysiology of aging and hypertension. Deficiency of the vascular extracellular matrix protein MFAP4 (microfibrillar-associated protein 4) has previously been observed as protective against aberrant arterial remodeling. We hypothesized that MFAP4-deficiency would reduce age- and hypertension-dependent arterial changes in extracellular matrix composition and stiffening.

METHODS: Mesenteric arteries were isolated from old (20-23 months) littermate Mfap4+/+ and Mfap4-/- mice, and 2-photon excitation microscopy imaging was used to quantify elastin and collagen volumes and dimensions in the vascular wall. Ten-week-old littermate Mfap4+/+ and Mfap4-/- mice were subjected to 20 days of continuous Ang II (angiotensin II) infusion and hypertension was monitored using invasive blood pressure measurements. Arterial stiffness, responses to vascular constrictors, and myogenic tone were monitored using wire- or pressure-myography. Collagen contents were assessed by Western blotting.

RESULTS: MFAP4-deficiency significantly increased collagen volume and elastin fragmentation in aged mesenteric arteries without affecting arterial stiffness. MFAP4-deficient mice exhibited reduced diastolic pressure in Ang II-induced hypertension. There was no significant effect of MFAP4-deficiency on mesenteric artery structural remodeling or myogenic tone, although collagen content in mesenteric arteries was tendentially increased in hypertensive Mfap4+/+ mice relative to Mfap4-/- mice. Increased efficacy of vasoconstrictors (phenylephrine, thromboxane) and reduced stiffness were observed in Ang II-treated Mfap4-/- mouse mesenteric arteries in ex vivo myography recordings.

CONCLUSIONS: MFAP4-deficiency reduces the elastin/collagen ratio in the aging resistance artery without affecting arterial stiffness. In contrast, MFAP4-deficiency reduces the stiffness of resistance arteries and ameliorates Ang II-induced hypertension.

Original languageEnglish
JournalHypertension (Dallas, Tex. : 1979)
Volume81
Issue number6
Pages (from-to)1308-1319
ISSN0194-911X
DOIs
Publication statusPublished - Jun 2024

Keywords

  • Animals
  • Hypertension/physiopathology
  • Mice
  • Mesenteric Arteries/physiopathology
  • Vascular Stiffness/physiology
  • Vascular Resistance/physiology
  • Aging/physiology
  • Angiotensin II/pharmacology
  • Elastin/metabolism
  • Blood Pressure/physiology
  • Extracellular Matrix Proteins/metabolism
  • Mice, Knockout
  • Disease Models, Animal
  • Male
  • Collagen/metabolism

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