09. Atherosclerosis

• atherosclerosis = pathological process that damages the major arteries and leads to cardiovascular disease
• stroke = fragments of plaque become dislodged and enter the circulation, cause further occlusion upstream
• atherosclerosis occurs in large arteries, especially at bifurcations due to turbulent flow

  • regions of low sheer stress and turbulent flow lead to endothelial dysfunction making the endothelium more permeable
  • allows lipoproteins to gain access to subendothelial space where plaque formation occurs
• if atherosclerotic plaques form at the carotid bifurcation this requires stenting or an angioplasty
• in healthy arteries, nitric oxide is continually produces by the endothelium to provide good vascular tone
• when an atherosclerotic lesion develops, deposition of lipid material in the subendothelial space occurs
• stabilisation of plaque occurs as smooth muscle cells produce lots of ECM proteins like collagen or elastin which wall of the plaque structure

  • can be treated with diet and statins to remove
• cell types in plaques:

  • endothelial cells
  • smooth muscle cells
  • platelets
  • macrophages
  • CD4+ helper T cells
• endothelial layers:

  • intima = where plaque develops
  • media = lots of smooth muscle cells that provide stiffness and contractility
  • adventitia = vessels that supply blood to arteries and lymph structures
• endothelial cells have the capacity to bind LDL and translocate LDL to the sub-endothelium
• endothelial cells secrete important mediators like vasodilators, vasoconstrictors, pro-thrombotic and anti-thrombotic components
• endothelial cells have mechanosensors that detect changes in flow patterns

  • activate endothelial cells
  • upregulate adhesion molecules to allow for lymphocytes to enter the tissue
• when the endothelium is activated it becomes permeable, allowing LDL to gain access to the intima

  • LDL undergoes oxidation and feedbacks onto endothelial cells to promote their activation
• factors released by endothelial cells:

  • vasodilators like nitric oxide and prostacyclin
  • vasoconstrictors like endothelin and angiotensin II
  • anti-thrombotic factors like tPA
  • prothrombotic factors like thromboxane A2
• platelets are small cytoplasmic fragments of megakaryocytes

  • play key role in endothelial cell repair
  • adhere to sub-endothelium via collagen receptors
  • important when plaque ruptures - platelets are first responders to seal off the plaque to form a plug
• vascular smooth muscle cells:

  • provide muscular arteries with their elasticity
  • play key role in regulating blood pressure
  • secrete elastin and collagens in stable plaques
  • macrophage induced smooth muscle cell apoptosis seen in vulnerable plaques
• once mature, macrophages accumulate modified LDL via scavenger receptors

  • macrophage foam cells are the main cell type in fatty streak lesions
  • secrete inflammatory mediators and growth factors
• some macrophages produce more MMPs if they are inflammatory in nature

  • causes breakdown of collagen and elastin leading to thinning of fibrous cap of plaque making it unstable
• macrophage upregulates scavenger receptor which allow assimilation of LDLs forming foam cells

  • keeps engulfing lipid
  • becomes engorged and undergoes apoptosis
• initiation of atherogenesis:

  • LDL transported to sub-endothelial space as the endothelial permeable
  • LDLs undergo modifications - macrophages can target these more easily.
  • macrophages uptake LDL via scavenger receptors
• atherogenesis progression:

  • development of lipid rich necrotic core as foam cells are undergoing apoptosis due to engulfing too much lipid
  • SMCs generate lots of ECMs to generate a fibrous cap
  • partial arterial stenosis
• lipoproteins are classified based on density

  • chylomicrons in liver
  • very low density lipoprotein (VLDL)
  • intermediate density lipoprotein (ILD)
  • low density lipoprotein (LDL)
  • high density lipoprotein (HDL)

  VLDL, IDL and LDL are pro-atherogenic

  HDL is anti-atherogenic (antioxidant properties)
• LDL cholesterol:

  • strongly associated with atherosclerosis and CVD
• HDL cholesterol:

  • low levels of HDL cholesterol associated with increased risk of CVD
  • mediates reverse cholesterol transport
  • important source of antioxidants
• modifiable risk factors for CVD include

  • high plasma LDL cholesterol
  • hypertension
  • smoking
  • diabetes
• non-modifiable risk factors of CVD

  • family history
  • advanced age
  • gender
• genetic predispositions to CVD:

  • familial hypercholesterolaemia - deficiency in LDL receptor leading to increased LDL circulating levels
  • tangier disease - defective AC1 transporter, cannot promote cholesterol efflux