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1

introduce hamodynamics in relation to atherosclerosis and other risk factors.

Although the entire coronary tree is exposed to the atherogenic effect of the systemic risk factors, atherosclerotic lesions form at specific arterial regions where low and oscillatory endothelial shear stress (ESS) occur.
Local factors, such as haemodynamic forces, play a major role in the regional localisation of atherosclerosis - ESS being the fundamental factor.
Hemodynamic factors can modulate the gene expression and phenotype of vascular ECs in vitro and in vivo.

2

what are the main models/types of models and areas of research for investigating the effects of haemodynamics on atherogenesis?

Autopsy-based models of fluid dynamics in coronary arteries, carotid bifurcations, distal abdominal aortas show that areas with LOW ESS correlate to the localisation of atherosclerosis found at autopsy. Further support of the atherogenic role of low ESS is also derived from in vivo experiments in animal models.

Molecular and cellular studies have begun to clarify the detailed pathways by which low ESS leads to atherosclerosis.

Animal models to create disturbed flow: the introduction of a local stenosis by constricting a segment of a lrage vessel. The creation of arteriovenous fistula (AVF). The AVF causes low and oscillating wall shear stress in zones where flow stagnation occurs on the outer wall of the artery and on the inner wall of the juxta-anastomotic site.

3

what is the endothelial shear stress and what factors does it depend on?

Endothelial shear stress is the tangential stress derived from the friction of the flowing blood on the endothelial surface. The nature of fluid flow through a tube is dependent on the velocity of flow and the presence of geometric irregularities or obstructions.

4

what types of flow are there and what are their characteristics?

Fluid flow can be either laminar or turbulent.
Laminar flow refers to streamlines flow and can be further divided into undisturbed, characterised by smooth streamlines, and disturbed laminar flow, characterised by areas of reversed flow, or circumferential swirling.
In turbulent flow the velocity at any given point varies continuously over time, even though the overall flow is steady.

5

describe LOW ESS:

Low ESS refers to ESS that is unidirectional at any given point but has a periodically fluctuating magnitude that results in a significantly low time-average.
Low ESS typically occurs at the inner areas of curvatures as well as upstream of stenoses.

6

describe OSCILLATORY ESS:

characterised by significant changes in both directions and magnitude between systole and diastole, resulting in a very low time-average. Occurs priamrily downstream of stenoses, at the lateral walls of bifurcations, and in the vicinity of branch points.

7

what is the relative importance of oscillatory and low ESS?

Although low and oscillatory ESS are closely assocaited with atherogenesis, the relative importance of these different ESS patterns is unclear.
In a mouse carotid artery in vivo model, both types of flow led to atherosclerotic plaque formation, but only low nonoscilatory ESS was associated with inflammatory changes and proclivity to rupture. Different vascular territories might also respond differently to various ESS stimuli.

8

describe mechanotransduction

Endothelial cell (EC) surfaces are equipped with numerous mechanoreceptors capable of detecting and responding to ESS stimuli, whereby activation of mechanosensitive receptors results in the induction of a complex network of intracellular pathways - a process known as mechanotransduction.

9

what is the common effector for multiple mechanotransduction pathways?

These pathways are activated simultaneously and cross-talk with each other, the great majority of them converge into mitogen-activated protein kinase (MAPK) cascade at various levels, suggesting that MAPK has a key role in mechanotransduction.

10

what biomarkers are the hallmark of atherogenesis?

Increased expression of biomarkers such as MCP-1, VCAM-1, ICAM-1, and E-elsectin are a hallmark of the endothelial inflammatory phenotype in atherosusceptible regions,

11

generally, what happens in disturbed vs laminar flow in terms of gene expression?

n regions of non-disturbed flow, atheroprotective genes are expressed, suppressing pro-atherogenic ones, leading to stability and quiescence of the area, in contrast, low and disturbed flow upregulates pro-atherogenic genes and suppresses atheroprotective ones.

12

list the effects of low ESS on vasculature

1. Low ESS attenuates NO-dependent atheroprotection.

2. Low ESS promotes LDL cholesterol uptake, synthesis and permeability

3. Low ESS promotes oxidative stress

4. Low ESS promotes inflammation

5. Low ESS promotes vascular smooth muscle cell migration, differentiation, proliferation

6. Low ESS promotes ECM degradation in vascular wall and plaque fibrous cap

7. Low ESS attenuates ECM synthesis in vascular wall and fibrous cap of the plaque.

8. Indirectly promotes neovascularisation

13

limitations of studying homogeneous cell cultures

Current analyses have suggested that endothelial phenotypes are highly heterogeneous over different regions of the arterial trees. Analyses on homogenates of endothelium may mask and neutralise the changes in cells of interest because of the presence of cells with different behaviours in neighboring locatioions. Therefore, spatial and temporal studies on genomic and epigenomic profiling at single cell level would be a fruitful future direction.

14

1. Low ESS attenuates NO-dependent atheroprotection:

1. Low ESS attenuates NO-dependent atheroprotection.
a. NO possesses strong anti-inflammatory, antiapoptotis, antimitogenic andtithrombotic properties
b. Dusturbed flow --> decreased eNOS mRNA and protein expression
c. Downregulates prostacyclin and Upregulates endothelin-1 --> also promotes thrombogenicity

15

2. Low ESS promotes LDL cholesterol uptake, synthesis and permeability

2. Low ESS promotes LDL cholesterol uptake, synthesis and permeability
a. Low ESS causes a sustained endothelial activation of sterol regulatory elements binding proteins (SERBPs) - a family of transcription factors that upregulate the expression of genes encoding LDL receptor, cholesterol synthase, fatty acid synthase => results in an increased engagement and syntehhsis of LDL by Ecs, promoting subendothelial accumulation of LDL.
b. SERBPs also appear to induce IL-8 and thus monocyte accumulation into the intima
c. In additon, disturbed flow increases the permeability of the endothelial surface to LDL
d. Low ESS promotes mitotic and apoptotic EC activity, thus creating small gaps between the ECs facilitating the infiltration of LDLs

16

3. Low ESS promotes oxidative stress

3. Low ESS promotes oxidative stress
a. Enhances gene expression and post-transcriptional activity of the major oxidative enzymes
b. Also appears to downregualte intracellular ROS scavengers
i. Generated ROS degrade NO

17

4. Low ESS promotes inflammation

4. Low ESS promotes inflammation
a. The recruitment of inflammatory cells into intima to scavenge oxidised LSL constitutes a major pathogenic component in the atherosclerosis
b. Low ESS has an immportant role in activating certain transcription factors, notably the NF-kB. NF-kB upregulates various proinflammatory genes, including several adhesion molecules: VCAM-1, ICAM-1, E-selecrtin, chemoatractant chemokines (MCP-1),and proinflammatory cytokines such as TNF-alpha and IL-1.
i. Adhesion molecules are expressed on EC surface and mediate rolling and adhesion of circulating leukocytes, whereas MCP-1 promotes transmigraiton of leukocytes into intima.

18

6. Low ESS promotes ECM degradation in vascular wall and plaque fibrous cap

6. Low ESS promotes ECM degradation in vascular wall and plaque fibrous cap
a. Upregulates gene expression and activity of matric metalloproteinases (MMPS), particularly MMP2 and MMP9, which are major proteases associated with EMC degradation in atherosclerotic plaques. Proinflammatory cytokines (TNF-alpha, IL-1, INF-gamma) comprise the major stimuli for the release of MMPs from their key cellular sources.
b. Low ESS enhances the accumulation of macrophages and VSMC within the plaque where the upregulated pro-inflammatory cytokines stimulate them to secrete MMPs

19

8. Indirectly promotes neovascularisation

by inducing intimal thickening nad thus ischaemia --> upregulating VEGF and other angiogenic factors