Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Jan 7;12(2):253.
doi: 10.3390/cells12020253.

Milk Fat Globule Epidermal Growth Factor VIII Fragment Medin in Age-Associated Arterial Adverse Remodeling and Arterial Disease

Mingyi Wang  1 , Kimberly R McGraw  1 , Robert E Monticone  1
Affiliations
Review

Milk Fat Globule Epidermal Growth Factor VIII Fragment Medin in Age-Associated Arterial Adverse Remodeling and Arterial Disease

Mingyi Wang et al. Cells. .

Abstract

Medin, a small 50-amino acid peptide, is an internal cleaved product from the second discoidin domain of milk fat globule epidermal growth factor VIII (MFG-E8) protein. Medin has been reported as the most common amylogenic protein in the upper part of the arterial system, including aortic, temporal, and cerebral arterial walls in the elderly. Medin has a high affinity to elastic fibers and is closely associated with arterial degenerative inflammation, elastic fiber fragmentation, calcification, and amyloidosis. In vitro, treating with the medin peptide promotes the inflammatory phenotypic shift of both endothelial cells and vascular smooth muscle cells. In vitro, ex vivo, and in vivo studies demonstrate that medin enhances the abundance of reactive oxygen species and reactive nitrogen species produced by both endothelial cells and vascular smooth muscle cells and promotes vascular endothelial dysfunction and arterial stiffening. Immunostaining and immunoblotting analyses of human samples indicate that the levels of medin are increased in the pathogenesis of aortic aneurysm/dissection, temporal arteritis, and cerebrovascular dementia. Thus, medin peptide could be targeted as a biomarker diagnostic tool or as a potential molecular approach to curbing the arterial degenerative inflammatory remodeling that accompanies aging and disease.

Keywords: cardiovascular disease; cardiovascular remodeling; cerebrovascular cognitive decline and dementia; degenerative inflammation; medin.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic of MFG-E8, medin, and medin amyloid formation. (A) MFG-E8 is a secreted glycoprotein and is also termed lactadherin. Human MFG-E8 contains an EGF-like domain on the N-terminal side and two repeated domains homologous to blood coagulation factor V/VIII (C1 and C2 domains, respectively) on the C-terminal side. Medin is a 50-amino acid peptide cleaved by unknown mechanisms from the C2 domain of MFG-E8. (B) An in vitro assay of medin aggregation state in three phases: the lag phase, growth phase, and plateau phase. MFG-E8, milk fat globule EGF VIII; EGF, epidermal growth factor; C1, discoidin-like domain 1; C2, discoidin-like domain 2; RGD, an Arg-Gly-Asp motif. Created with BioRender.com.
Figure 2
Figure 2
MFG-E8 expression in the aortic wall. (A) Bulk human tissue expression for MFG-E8 from the genotype-tissue expression (GTEx) project (version 8) (http://gtexportal.org/omr/ (accessed on 23 October 2022)), showing that MGF-E8 is highly expressed in arteries, especially in the aorta. (B) Immunostaining MFG-E8 in the aortic walls in aging rats, nonhuman primates and human samples, modified from Wang M et al. [10]. MFG-E8, milk fat globule EGF VIII. L, lumen; M. media. Created with BioRender.com.
Figure 3
Figure 3
Elastin-contractile unit in the vascular wall. A schematic depiction of remodeling of the arterial elastin-contractile unit with aging, focusing on MFG-E8/medin. MFG-E8/medin acts as a bridging molecule (linker) between the elastic lamina and VSMCs which is involved in the stiffening of the vascular elastin-contractile microstructure with aging. Cleavage of MFG-E8 to release medin will break this bridge/linkage. Medin may compete with MFG-E8 in the binding to elastic fiber forming a linear amyloid fibril or aggregates as a non-amyloid oligomer, which promotes vascular microstructure stiffening in advanced age. ECM, extracellular matrix; VSMCs, vascular smooth muscle cells; MFG-E8, milk fat globule EGF VIII. Created with BioRender.com.
Figure 4
Figure 4
MFG-E8/Medin-mediated vascular cellular inflammation and vascular dysfunction. (1) Aging increases the expression of MFG-E8 and medin; (2) MFG-E8/medin activates the inflammatory reaction and oxidative stress through the RAGE receptor in endothelial cells and triggers the inflammation and oxidation in vascular smooth muscle cell via receptors integrin and oligomer medin forming the membrane pore; (3) MFG-E8/medin associated oxidative and nitrative stress and inflammation eventually leads to the apoptosis, senescence, and necrosis of both ECs and VSMCs; and (4) Vascular inflammatory phenotypic shifts cause vascular endothelial dysfunction (acetylcholine dependent dilatation decline) and vascular stiffening. Abbreviations: MFG-E8, milk fat globule EGF VIII; EC, endothelial cells; IEL, internal elastic lamina; VSMC, vascular smooth muscle cells; RAGE, receptor for advanced glycation end-product; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IL-6, interleukin-6; IL-8, interleukin-8; ICAM1, intercellular adhesion molecule 1; VCAM1, vascular cellular adhesion molecular 1; PAI 1, plasminogen activator inhibitor 1; ROS, reactive oxygen species; RNS, reactive nitrative species; SO, superoxide; NO, nitric oxide; MMP-2, matrix metalloproteinase type-2; MMP-9, matrix metalloproteinase type-9; TGF-β1, transforming growth factor-beta 1; BMP-2, bone morphogenetic protein-2; SMAD-2/3, suppressor of mothers against decapentaplegic-2/3; ALP, alkaline phosphatase; Runx2, runt-related transcription factor-2; HO-1, heme oxygenase; NQO1, NAD(P)H quinone dehydrogenase-1; Nrf2, nuclear factor erythroid 2-related factor. Created with BioRender.com.
Figure 5
Figure 5
The Role of MFG-E8 Fragment Medin in Age-Associated Arterial Disease. (1) Aging increases MFG-E8 and its fragment medin during inflammatory remodeling; (2) Medin drives the inflammatory phenotypic shifts of ECs and VSMCs, and medin inflammation modifies the vascular extracellular matrix such as through amyloidosis, elastic fragmentation, and calcification; (3) Medin inflammatory signaling promotes vascular wall weakness, endothelial-dependent relaxation decline and arterial stiffening; (4) Medin is involved in the development of vascular diseases, aortic aneurysm/dissection, arteritis, and vascular dementia. MFG-E8, milk fat globule EGF VIII; EC, endothelial cells; VSMCs, vascular smooth muscle cells. Created with BioRender.com.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Degenhardt K., Wagner J., Skodras A., Candlish M., Koppelmann A.J., Wild K., Maxwell R., Rotermund C., von Zweydorf F., Gloeckner C.J., et al. Medin aggregation causes cerebrovascular dysfunction in aging wild-type mice. Proc. Natl. Acad. Sci. USA. 2020;117:23925–23931. doi: 10.1073/pnas.2011133117. - DOI - PMC - PubMed
    1. Karamanova N., Truran S., Serrano G.E., Beach T.G., Madine J., Weissig V., Davies H.A., Veldhuizen J., Nikkhah M., Hansen M., et al. Endothelial Immune Activation by Medin: Potential Role in Cerebrovascular Disease and Reversal by Monosialoganglioside-Containing Nanoliposomes. J. Am. Heart Assoc. 2020;9:e014810. doi: 10.1161/JAHA.119.014810. - DOI - PMC - PubMed
    1. Wang M., Jiang L., Monticone R.E., Lakatta E.G. Proinflammation: The key to arterial aging. Trends Endocrinol. Metab. 2014;25:72–79. doi: 10.1016/j.tem.2013.10.002. - DOI - PMC - PubMed
    1. Migrino R.Q., Karamanova N., Truran S., Serrano G.E., Davies H.A., Madine J., Beach T.G. Cerebrovascular medin is associated with Alzheimer’s disease and vascular dementia. Alzheimer’s Dement. 2020;12:e12072. doi: 10.1002/dad2.12072. - DOI - PMC - PubMed
    1. Kim S.H., Monticone R.E., McGraw K.R., Wang M. Age-Associated Proinflammatory Elastic Fiber Remodeling in Large Arteries. Mech. Ageing Dev. 2021;196:111490. doi: 10.1016/j.mad.2021.111490. - DOI - PMC - PubMed

Publication types

-