_Dr. Powell's lecture_pmi_285_2004_lecture_2

_Dr. Powell's lecture_pmi_285_2004_lecture_2 - PMI 285 ­...

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Unformatted text preview: PMI 285 ­ Winter 2004 Cellular Basis of Disease PMI 285 ­ Winter 2004 Cellular Basis of Disease Vascular Response to Injury 1. Hypertrophy increase in the size of individual cells 2. Hyperplasia increase in the number of cells 3. Vascular remodelling sculpting of the vessel itself What is hypertension ? What is hypertension ? • Human: blood pressure of > 130/80 mm Hg Why ? Not known. Generally, we treat the symptoms, not the causes. How does the vasculature respond ? Response to hypertension Response to hypertension • Acute increase: detectable injury ­ arterioles increased numbers of cells increased extracellular matrix deposition reversible • Chronic increase: no discernible difference gradual hypertrophy gradual increase in matrix loss of elasticity due to matrix changes difficult to reverse, perhaps possible Why is the response problematic ? Why is the response problematic ? • increased matrix interferes with function nutrient diffusion arteriolar bed distribution • heart failure why not understood. Arteriosclerosis Injury hypothesis Step 1 ­ Cholesterol (atherosclerosis) ­ Virus Cytomegalovirus ­ Metabolic homocysteine ­ Mechanical hypertension Leukocyte adhesion Endothelial Leukocyte Endothelial permeability migration adhesion Arteriosclerosis Injury hypothesis Step 2 Result of repeated injury Platelet adherence Monocyte SMC Foam cell aggregation migration T cell formation activation Arteriosclerosis Injury hypothesis Step 3 1. Macrophage accumulation is: Rate in minus Rate out 2. On­going T cell activation Fibrous cap Macrophage Formation of formation accumulation Necrotic core Arteriosclerosis Injury hypothesis Step 4 End stages – 20 years ­ Heart attacks ­ Strokes ­ Peripheral vascular problems Plague Rupture Thinning of fibrous cap Neoangiogenesis And microbleeding Vascular Response to Vascular Response to Denudation Injury 1. Denudation of endothelium ­ immediate 2. Response in Media of smooth muscle cells ­ over 2 days a. Phenotype change b. Proliferation c. Migration Vascular Response to Vascular Response to Denudation Injury 3. Intimal response a. Proliferation b. Extracellular matrix production 4. Vascular remodelling ­ long term (months) a. Re­endothelialization b. Apoptosis Vascular Response to Vascular Response to Denudation Injury – when the response becomes pathological Migration Extracellular matrix Proliferation Remodelling Re­endothelialization Endothelial dysfunction Ad­Rbz­Bcl­2 inhibits neointima formation in the rat Ad­Rbz­Bcl­2 inhibits neointima formation in the rat carotid artery model of VSMC hyperplasia. Cross­sections of common carotid arteries, treated with 1 x 10 pfu adenovirus for 20 min. after denudation, analyzed at 14 d. Ad­β ­gal Ad­Rhz­Bcl­2 Media Lumen Neointima Media Lumen Control artery Treated artery Percutaneous Transluminal Coronary Angioplasty ­ Restenosis 1980 – mechanical dilation of blocked artery ­ approaches to “destroy” the atheroma Late 1980’s – trials to block SMC migration and/or SMC proliferation 1. heparin 2. ACE inhibition 1990’s – chemotherapy, radiation implants Percutaneous Transluminal Coronary Angioplasty ­ Restenosis revisited Mid­1990’s – vascular remodelling stents placed with enlarged lumen 2003 – combination approaches: stents with “slow release” chemotherapy ...
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