An Example of Ongoing Investigations of the Biochemical Details of Arterial Stiffening

The functions of many important tissues in the body depend on physical properties such as elasticity or ability to bear load. These properties derive from the particular structure of the extracellular matrix formed by a tissue, an arrangement of proteins constructed as a mesh to surround and support the cells it holds. The structural properties of the extracellular matrix are increasingly degraded over the course of aging, however, such as by the formation of advanced glycation end-products (AGEs) that can link together proteins of the extracellular matrix in ways that alter the physical properties of the tissue. In the case of blood vessels, rising levels of these cross-links lead to a progressive loss of elasticity, and that in turn causes a whole range of issues in the cardiovascular system that start at hypertension and culminate in catastrophic structural failure of the heart or important blood vessels.

Biochemistry is as a rule always more complicated than we'd like it to be, and so there are many areas of open investigation when it comes to the chemistry of stiffening blood vessels. Metabolic waste products come in many varieties, and it isn't always the case that any given class is actually doing what it is thought to do. Small consensus positions are quietly overturned on a daily basis at the edges of the field, given the falling costs of performing the necessary work, and the foundations of tomorrow are being built beneath the notice of even most researchers.

One of the more important lines of research at the moment, for all that is has little funding and is paid little attention, is to create the means for more research groups to work on glucosepane in human tissues. This appears to be the most prevalent type of AGE forming cross-links in our species - and here it is worth noting that a part of the complexity of this issue is that the chemistry of extracellular matrix cross-linking is very different in various different mammalian species. Lessons learned in mice are only relevant in a very general sense. You'll see few papers on glucosepane despite its importance in our biochemistry, as good tools for working with the class of compounds that glucosepane belongs to in the context of cells and tissues really don't exist yet. For a variety of not-so-good reasons no major research establishment has yet turned its eyes to building them, and so it has fallen on forward-thinking philanthropy to bridge the gap.

As I said, however, there are a lot of different waste products: it is a large space to explore. Those researchers not working on glucosepane are putting in time on other chemicals thought to be relevant to the issue of blood vessel stiffening, but they often draw a blank or find that presence of waste in cells doesn't necessarily correspond to a significant impact on the function of the extracellular matrix, as is the case here. That may not always be the case, of course, and there are certainly good reasons to think that stiffening isn't just AGEs. Science is as much a process of opening doors to empty rooms as it is of finding the one that hides the goal.

Elastin aging and lipid oxidation products in human aorta

In normal arteries, the proteins of the extracellular matrix (ECM) (collagen, elastin, fibrillin, glycoproteins and proteoglycans) produced by smooth muscle cells (SMC) ensure the stability, resilience, and compliance of arteries. Collagen and elastin, two major scaffolding ECM proteins provide structural integrity and elasticity to the vessels, allowing them to stretch while retaining their ability to return to their original shape when the pressure is over. Vascular aging is most of the time associated with structural and functional modifications of the arteries, even in healthy elderly, and particularly by an increase in arterial wall thickening in the intima and the media, mainly resulting from the accumulation and structural modification of ECM components and a disorganization of SMC.

Arterial stiffness is characterized by structural and functional alterations of the intrinsic elastic properties of the arteries and an increased resistance to vessel deformation, resulting from a decrease in artery elasticity (compliance) and an increase in pulse wave velocity (pwv), generating an increased systolic pressure, with deleterious consequences on the heart, generating cardiac hypertrophy and increased ventricular oxygen consumption. Arterial stiffening is a hallmark of vascular aging, and a major risk factor for the development of cardiovascular diseases, that can be exacerbated by diabetes, hypertension or atherosclerosis. It is a direct cause of ventricular hypertrophy, renal dysfunction and stroke, independently of the other causes of vascular aging. It is an independent risk factor for cardiovascular diseases, which may predispose to atherosclerosis, and vice-versa.

Among the factors known to accumulate with aging, advanced lipid peroxidation end products (ALEs) are a hallmark of oxidative stress-associated diseases such as atherosclerosis. Aldehydes generated from the peroxidation of polyunsaturated fatty acids (PUFA) form adducts on cellular proteins, leading to a progressive protein dysfunction with consequences in the pathophysiology of vascular aging.

The contribution of these aldehydes to ECM modification is not known. This study was carried out to investigate whether aldehyde-adducts are detected in the intima and media in human aorta, whether their level is increased in vascular aging, and whether elastin fibers are a target of aldehyde-adduct formation. Immunohistological and confocal immunofluorescence studies indicate that [these] adducts accumulate in an age-related manner in the intima, media and adventitia layers of human aortas, and are mainly expressed in smooth muscle cells. In contrast, even if the structure of elastin fiber is strongly altered in the aged vessels, our results show that elastin is not or very poorly modified by [these adducts].

Comments

It may be worth noting that enzymatic crosslinking in vascular tissues, which increases with age, can be reduced by exercise. See -

"Exercise, Vascular Stiffness, and Tissue Transglutaminase"
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4187484/

"How Old are Your Arteries? Exercise‐Mediated Protection From Age‐Associated Vascular Stiffness"
http://jaha.ahajournals.org/content/3/2/e000941.short

"The Role of Transglutaminase-2 in Vascular Stiffness"
http://sens.org/outreach/conferences/role-transglutaminase-2-vascular-stiffness

Posted by: Lou Pagnucco at January 4th, 2015 10:32 PM

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