Site Specificity of Atherosclerosis

Site-Selective Responses to Atherosclerotic Modulators

Paul A. VanderLaan,

Catherine A. Reardon,

Godfrey S. Getz

From the Department of Pathology, University of Chicago, Chicago, IL.

Correspondence to Godfrey S. Getz, University of Chicago, Department of Pathology MC 1089, 5841 S Maryland Ave, Chicago, IL 60637. E-mail [email protected]

Abstract

Atherosclerosis is a complex disease process that affects very specific sites of the vasculature. It is recognized that hemodynamic forces are largely responsible for dictating which vascular sites are either susceptible or resistant to developing atherosclerosis. In addition, a number of systemic and local factors also modulate the pathogenesis of the disease. By studying the development of atherosclerosis in mice, investigators have gained insights into the molecular mechanisms of this disease, although studies have largely focused on a single vascular site. Here, we review those recent studies in which vascular site-specific effects on atherosclerosis were reported when more than 1 site was examined. We assess the hypothesis that regional differences in the hemodynamic profile prime the endothelial phenotype to respond distinctly to such systemic risk factors as hypercholesterolemia, genetics, immune status, gender, and oxidative stress. Because a given treatment may differentially affect the development of atherosclerotic lesions throughout the vasculature, the sites chosen for study are critically important. By accounting for the complex interplay of factors that may operate at these different sites, a more complete understanding of the overriding mechanisms that control the initiation and progression of the atherosclerotic lesion may be realized.

For more plz read at following link.

Regards

http://atvb.ahajournals.org/content/24/1/12.full

Atheroma site specificity correlates strongly with regions of disturbed shear stress, I.e. on the outer wall at a flow divider, e.g. bifurcation - where shear is low, or at regions of vessel curvature, e.g the aortic arch. Also, contrary to popular believe, shear is not uniform across the circulation. In fact, it is considerably higher in small arteries and especially arterioles. Also, between species there is an inverse relation between shear and body mass, e.g. shear is around 15 times higher in the abdominal aorta of a rat than the same region in a human. Coincidence that rats don't spontaneously develop atheroma?? Notably, shear is a powerful inducer and suppressor of the genes pertaining to vasodilation and vascular disease. 

Hope that helps,

Dave

 Dear All,

Atherosclerosis at specific sites in the arterial wall  has been observed since the time of Anitschkow’s cholesterol-fed rabbits.

Steinberg D: Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: Part I. J Lipid Res. 45:1583-1593 2004

Dear Dr Ali A R Aldallal,

Thanks for the article. Yes, shear stress is important but 2 arteries with the same shear stress behave very differently in the same individual. The article you sent seems to have summarised it reasonably well

"Hemodynamic features play a major role in the localization of atherosclerotic lesions within the vascular tree, but they are not by themselves responsible for the genesis of atherosclerosis. We postulate that hemodynamic parameters probably differ in some respects at the various high-susceptibility sites, namely, in the extent of oscillation, turbulence, or level of shear in their respective flow fields. Such regional differences may prime the local vascular wall and its gene-expression profile to differentially interact with systemic factors, thereby resulting in the potential for variations in atherosclerotic outcomes at these local sites."

Dear Dr David C. Ellinsworth ,

Thanks for your insights. About rats not getting atheroma despite 15 times higher stress...Maybe they just dont live long enough for atherosclerosis to manifest. Importantly, rats are very efficient in converting cholesterol to bile acids. Consequently, even on very high cholesterol intakes the blood cholesterol in these species does not increase appreciably. So, despite the shear stress, the metabolism does not favour atherogenesis very much.

Dear Dr Paulo Eduardo Ocke Reis,

Dr Anitschkow's work on cholesterol fed rabbits is indeed legendary and the article is a great read. But my question was not about atherosclerosis and cholesterol but rather about the "site specificity" of these lesions. For eg How come the left carotid has a severe lesion with the same shear stress while the right carotid is spared in a given indidual while the reverse is true in another (i.e right is involved and left is spared! I was intrigued by the seeming randomness and asymmetry and not the presence of atherosclorosis itself! This aspect was not touched upon at any time by Dr Anitschkow.

regards

Do atheroma form in straight sections of the left carotid artery?

 Carotid atherosclerosis is usually most severe within 2 cm of the bifurcation of the common carotid artery, and predominantly involves the posterior wall of the vessel. The plaque encroaches on the lumen of the internal carotid artery and often extends caudally into the common carotid artery. An hourglass configuration to the stenosis typically develops with time.

Atheromas can extend towards the straight sections from the bifurcation. However, if you are asking whether atheroma can occur in straight sections in absence of involvement of bifurcation, I would hazard a guess that it is possible but would be markedly less common. I do not know the correct answer to this aspect.

regards

That is most likely to do with disturbed shear. However, like you said, it doesn't quite explain the difference between the two carotids. Or at least not necessarily. Maybe time averaged shear is similar between the two, but there is more profound oscillatory shear or regional high/low shear regions. I still maintain that it's something haemorheological. Maybe there is more atherprotective gene expression in one vs the other. By analogy, in my field there are highly artery-specific mechanisms of EDH-mediated vasodilation. The expression of signalling components geared to drive this mechanism may not be present in one artery vs another. We know this can happen even between successive branches of the same vascular bed. Maybe something similar is happening here for atheroprotective. I doubt the shear profiles near the bifurcation are EXACTLY the same for both vessels. 

Blood flow in a blood vessel is what we can call as a "Complex system". Complex Systems Exhibit Chaotic Behavior that is is characterized by extreme sensitivity to initial conditions, fractal geometry, and self-organized criticality. In a complex system, there are many variables, and they are strongly interdependent. This makes it difficult to know exactly which inputs contribute to an observed output, and the extent of each factor's contributions.

The concept of sensitive dependence on initial conditions has been popularized in the so-called "butterfly effect": the idea that a butterfly flapping its wings in Brazil could change the weather in Texas. Minute differences in the initial conditions for such a system result in extremely different outcomes.

The asymmetry observed (whyone vessels gets AS while other does not) in what appears to be almost similar situation is possibly explained by looking at it as a complex system. This article, though not directly related to atherosclerosclerosis, does give an interesting insight on how complex systems work and some of its lessons can be exptrapolated to our situation here.

http://serc.carleton.edu/NAGTWorkshops/complexsystems/introduction.html

Of course, the driving arterial blood affects the walls of the arteries ([email protected] ). The influence can be viewed from two sides: from the side of dynamics and statics. From the dynamics side, it's really difficult. But the sides of statics - no one forbids us to consider, i.e. we must mentally stop the movement of blood. So, static:

1) in a vertically positioned tube (aorta, arteries - standing, sitting), the pressure forces on the inner layer at the bend of the aorta will be less than similar forces in the lower part of the aorta (F=m *g*h). This is equivalent to the statement that there are forces at the top of the separation of the inner layers of the arterial wall (endothelium) from the middle layers (from media and adventitia). And at the bottom, the forces of pressing these layers together. All this contributes to endothelial dysfunction (the onset of atherosclerosis) and rupture of the aorta, but after N years.

2) The forces contributing to atherosclerosis increase if, as a result of stress, the ABA-anastomoses open and there is a leakage of arterial blood into the veins.

Ermoshkin Vladimir Ivanovich. “The Mechanism of Atherosclerosis and Pathological Spasms of Human Arteries”. EC Cardiology 7.9 (2020): 69-74. https://ecronicon.com/eccy/ECCY-07-00750.php Vladimir Ermoshkin. “Possible Cause of Atherosclerosis from the Point of View of a Physicist”. EC Cardiology 8.6 (2021): 24-28. Ermoshkin V. I. "Eurasian Scientific Association", "Atherosclerosis occurs due to loss of arterial blood", No. 9 (67) • September, 2020. https://esa-conference.ru/wp-content/uploads/2020/10/esa-september-2020-part3.pdf