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Collagen type IV as the link between arterial stiffness and dementia.

ABSTRACT: Arterial stiffness has been linked to impaired cognitive function and dementia but the reason for the association is uncertain. This review proposes that collagen type IV is a critical factor linking arterial stiffness and dementia. Several genome wide association studies have related arterial stiffness to Collagen type IVα. Proteomic studies of arteries, demonstrated higher levels of collagen IVα1 in persons with high arterial stiffness. Collagen type IV defects are associated genetic causes of dementia as well as dementia of a variety of other causes. There are plausible causal roles for collagen type IV in dementia. Disorders of Collagen type IV can produce (I) fibro-hyalinosis and elastosis of small arterioles leading to cerebral ischemia and infarction; (II) dysfunction of the blood brain barrier leading to cerebral hemorrhage; (III) carotid artery stiffness with increase pulse pressure induces cerebral blood vessel damage leading to cerebral atrophy. The mechanisms by which Collagen type IV can lead to vascular stiffness include its degradation by matrix metalloprotease type 2 that (a) stimulates vascular smooth muscle cells to produce more extracellular matrix or (b) liberates peptides that damage the subendothelial space. Factors, such as TGF-β1, and LDL cholesterol especially oxidized LDL can increase collagen type IV and produce vascular stiffness and dementia. Fibroblast growth factor 23, and abnormal NO signaling have been linked to collagen type IV or increased vascular stiffness and an increased risk of dementia. Recognition of the central role of collagen type IV in arterial stiffness and dementia will inspire new research focused on determining whether its modification can benefit arterial and brain health.

SUBMITTER: Rabkin SW

PROVIDER: S-EPMC10641358 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Collagen type IV as the link between arterial stiffness and dementia.

Rabkin Simon W SW

American journal of translational research 20231015 10

Arterial stiffness has been linked to impaired cognitive function and dementia but the reason for the association is uncertain. This review proposes that collagen type IV is a critical factor linking arterial stiffness and dementia. Several genome wide association studies have related arterial stiffness to Collagen type IVα. Proteomic studies of arteries, demonstrated higher levels of collagen IVα1 in persons with high arterial stiffness. Collagen type IV defects are associated genetic causes of ...[more]

PMID: 37969177

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Project description:Arterial stiffening, a characteristic feature of obesity and type 2 diabetes, contributes to the development and progression of cardiovascular diseases (CVD). Currently, no effective prophylaxis or therapeutics is available to prevent or treat arterial stiffening. A better understanding of the molecular mechanisms underlying arterial stiffening is vital to identify newer targets and strategies to reduce CVD burden. A major contributor to arterial stiffening is increased collagen deposition. In the 5'-untranslated regions of mRNAs encoding for type I collagen, an evolutionally conserved stem-loop (SL) structure plays an essential role in its stability and post-transcriptional regulation. Here, we show that feeding a high-fat/high-sucrose (HFHS) diet for 28 wk increases adiposity, insulin resistance, and blood pressure in male wild-type littermates. Moreover, arterial stiffness, assessed in vivo via aortic pulse wave velocity, and ex vivo using atomic force microscopy in aortic explants or pressure myography in isolated femoral and mesenteric arteries, was also increased in those mice. Notably, all these indices of arterial stiffness, along with collagen type I levels in the vasculature, were reduced in HFHS-fed mice harboring a mutation in the 5'SL structure, relative to wild-type littermates. This protective vascular phenotype in 5'SL-mutant mice did not associate with a reduction in insulin resistance or blood pressure. These findings implicate the 5'SL structure as a putative therapeutic target to prevent or reverse arterial stiffening and CVD associated with obesity and type 2 diabetes.NEW & NOTEWORTHY In the 5'-untranslated (UTR) regions of mRNAs encoding for type I collagen, an evolutionally conserved SL structure plays an essential role in its stability and posttranscriptional regulation. We demonstrate that a mutation of the SL mRNA structure in the 5'-UTR decreases collagen type I deposition and arterial stiffness in obese mice. Targeting this evolutionarily conserved SL structure may hold promise in the management of arterial stiffening and CVD associated with obesity and type 2 diabetes.

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Collagen type IV as the link between arterial stiffness and dementia.

Publications

Collagen type IV as the link between arterial stiffness and dementia.

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