TA Reviews

Blood Vessels I

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M2

Pathology

TA Reviews

BLOOD VESSELS I Lecture Handout

Jill Conway, 9/18/00

Vascular disease causes about 50% of mortality in the US and significant morbidity as well.  General disease processes include narrowed or obstructed vessel lumen, and weakening of vessel wall potentially leading to rupture.

Normal Vessels:

Arteries are classified by size into large, elastic arteries (aorta, iliac, etc.), medium muscular arteries (coronary, renal) or small arteries that are less than 2 mm in diameter.

Elastic large arteries have lots of elastin in fiber layers within the media.  In muscular arteries, elastin is only in the elastic membranes.

Arterioles mainly determine TPR based on contraction or relaxation of smooth muscle.

Capillaries have a minor BM and no media.  Flow is slow because the total cross sectional area is high here compared to arterioles.

Veins are large and thin walled, with little IEM and media smaller than arteries.

Artery walls begin with the EC (endothelial cell) layer lining the intima.  There is some subendothelial connective tissue beneath the EC, then the fenestrated internal elastic membrane.  The media is composed mainly of smooth muscle cells.  The vasa vasorum extend through the outer half of the media in larger arteries.  The external elastic membrane delimits the media.  The adventitia is composed of connective tissue, vasa vasorum, and nerve fibers.

The main cellular components of vessel walls include ECs and SMCs.

EC activation:  ECs can respond to their environment.  Endothelial dysfunction = several types of potentially reversible changes in the functional state of ECs in response to environmental stimuli.  This is termed endothelial stimulation when rapid, reversible processes not involving protein synthesis occur, such as histamine mediated processes and NO release inhibition.  Dysfunction that involves changes in gene expression and protein synthesis are termed endothelial cell activation.  Inducers of endothelial activation are also risk factors for the development of atherosclerosis (AS), indicating the significance of EC function in clinical disease processes.

Vascular smooth muscle cells:  normally spindle shaped, with elongated nuclei.  SMCs are responsible for vasoconstriction and dilation, synthesizing collagen and elastin, producing growth factors, and both normal vascular wall function and pathological processes.  Growth promoters of SMCs include PDGF, bFGF, and IL-1.  Inhibitors include NO, IFN-gamma.

Intimal Thickening:  general response to injury

Minor intima damage can be repaired via endothelial cell proliferation and response, but if injury extends into the media, healing involves SMCs as well.  SMCs can be induced to migrate into the intima, proliferate, and lose much of their myosin contractile fibers.  Exaggerated healing is called intimal thickening and may reduce the normal lumen size of the vessel.

Fat metabolism review:

  1. Intestinal mucosa secrets chylomicrons full of triacylglycerols (TG) produced mostly from dietary intake.
  2. The liver produces VLDL which is another source of TG (considered to be endogenous).
  3. Elevated VLDL indicates hypertriglyceridemia = >200 mg/dl.
  4. Extracellular lipoprotein lipases degrades TG into free fatty acids in the tissues.  In the blood, lipoprotein lipase releases IDL and LDL from VLDL.  IDL and LDL carry cholesterol in the blood, so hypercholesterolemia is indicated by elevated LDL.
  5. LDL binds to receptors on extrahepatic tissues and on liver where they are endocytosed.  LDL is calculated as   LDL = serum CH - serum HDL - TG/5.  LDL <130 mg/dl is considered normal.  Total cholesterol of <200 mg/dl is considered normal.
  6. HDL carries apolipoprotein which can take up cholesterol from the tissues and plaques and recirculate it to the liver for excretion in the bile.   HDL is a negative risk factor and <35 mg/dl increases risk whereas >60 mg/dl is considered to be protective.

Arteriosclerosis:  thickening and loss of elasticity (sclerosis or rigidity) in arterial vessels.  There are three types of arteriosclerosis: atherosclerosis, Monckeberg’s, and arteriolosclerosis.  Clinically, atherosclerosis is by far the most important.

Monckeberg's medial calcific sclerosis:  calcifications in the media of medium sized muscular arteries in those over 50.  Does not change size of lumen and thus has little clinical significance.  However, arteries affected by calcifications may also be susceptible to atherosclerosis.

Arteriolosclerosis:  thickening of the small arteries and arterioles.  There are two types: hyaline and hyperplastic.  Hyaline arteriolosclerosis occurs in the elderly but is worse in those with HTN and DM.  Hyaline thickening occurs in the vessel walls with narrowing of the lumen.

Hyperplastic arteriolosclerosis is commonly associated with malignant HTN.  With ongoing injury, the vascular walls hypertrophy due to hyperplasia of SMCs and sometimes this occurs along with necrosis of the vessel wall.  There is a characterisitic “onion-skin” appearance of the vessel wall.

Atherosclerosis is responsible for >50% of US deaths; AMI causes about 20-25% of all deaths.  Atherosclerosis denotes disease of large and medium arteries in which there is intimal dysfunction with the formation of atheromas that may reduce the lumen size and also lead to dysfunction in the underlying media.

Atherosclerosis occurs as a progressive disease over time, beginning with the development of fatty dots and fatty streaks in childhood and potentially leading to complicated atherosclerotic plaques that can rupture, set up thrombosis and occlude the lumen.   Plaques are found most commonly in the lower abdominal aorta, coronary arteries, popliteal arteries, descending thoracic aorta, internal carotids and circle of Willis.  The aortic arch usually only gets plaques in the presence of an underlying condition like syphilitic aortitis.  Plaques often occur near the origins (ostia) of vessels leaving the aorta.

Atheromas, the lesions of atherosclerosis, are composed of a fibrous cap on the intimal surface consisting of SMCs, foam cells, collagen and elastin, and macrophages.  Underneath the cap is a central lipid core of necrotic cell debris, cholesterol crystals, foam cells, and calcium deposits.  The lipid in foam cells is primarily cholesterol in various forms.  Foam cells refer to the lipid laden intimal cells, usually originally macrophages, but may also arise from smooth muscle cells.

Major fixed risk factors are increasing age, males, genetic factors like familial hyperlipidemia.  Dyslipoproteinemias include genetic defects that influence one’s ability to process lipids in its various forms.

Acquired risk factors are hyperlipidemia (especially high cholesterol as shown by high LDL or high triglycerides as shown by high VLDL), hypertension, smoking, and diabetes.  LDL is increased by obesity and smoking.  HDL has a protective effect and is considered to be a negative risk factor and in increased by exercise and moderate ethanol use. 

Dietary intake of saturated fats and cholesterol increase risk of AS development.  Antioxidants and omega-3 fats are considered to be protective against development of AS.

Hypertension is a major risk factor and more important than hypercholesterolemia after age 45.

Smoking >1 pack per day for many years increase heart disease by >200%.  Note that quitting smoking reduces the increased risk, but does not eliminate it.

Diabetes increases risk of AMI, AS, strokes, and greatly increases the development of lower extremity atherosclerotic induced gangrene of the lower extremities.  Homocysteinuria also causes high plasma levels of homocysteine which may lead to EC disruption.

Risk factors are synergistic, not additive.

Current theory for how AS develops is the "response-to-injury" hypothesis which involves chronic endothelial injury, increased movement of lipoproteins into the vessel wall, cellular reactions involving ECs, monocytes, and SMC's, and proliferation of SMCs.

Injury may result from smoking, hyperlipidemia, immune reactions, toxins, viruses, or hemodynamic factors (turbulent flow).  Hyperlipidemia may disrupt the EC barrier and also makes oxidation of LDL more likely which gets taken up by macrophages by a scavenger receptor instead of being taken up by normal receptor.  In small vessels, this can cause occlusion (MI or CVA), and in larger ones an AS aneurysm, usually in the aorta just below the renal arteries.

Process:  chronic local endothelial injury leads to endothelial dysfunction with increased permeability and adhesion molecule expression.  Circulating lipoproteins may be taken into the vessel wall and the lipids can then be oxidized.  Monocytes adhere to the ECs and migrate into the intima.  Platelets may adhere to areas of EC interruption or to bound leukocytes.  Activated platelets, macrophages and ECs cause migration of SMCs into the intima where they proliferate and produce ECM with collagen.  SMCs and macrophages continue to take up lipids, becoming foam cells.

Macrophages play an enormous role in AS by 1) secreting toxic oxygen species that oxidize LDL, 2) secreting IL-1 and TNF (and PDGF) that increase adhesion of leukocytes and/or induce SMC proliferation and 3) may help in recruiting the T cells that are associated with atheromas.  The LDL gets taken up by the macrophages and excess lipid accumulates.  SMCs of the media migrate to the intima and take up excess lipid.  This produces the early fatty dots to fatty streaks which occur in the coronary arteries by age 10.  These streaks may regress or progress to become atheromas.

Swollen macrophages release lipid into the intima and cytokines from macrophages stimulate proliferation of myointimal cells that secrete collagen and elastin.  In addition, endothelial cells, smooth muscle cells, platelets, and macrophages secrete PDGF which works to induce proliferation of SMCs.  SMCs may secrete collagen and elastin as well, which makes the lesion harder and more fibrotic, contributing to the formation of a fibrous cap.  The lesion is now a mature fibrofatty atheroma that may continue to be lipid filled or increase the fibrotic reaction to become a fibrous plaque.  In longstanding lesions, the atheroma may eventually lose much of its lipid content and appear as a fibrotic scar.

The media undergoes pressure atrophy as the expanding intima pushes against it.  This leads to vessel wall weakness and increases the potential for aneurysm.  The endothelial wall of the intima is also weakened over an atheroma and will be more susceptible to rupture.

Plaques may have complications including

  1. calcification, especially common in advanced disease and may predispose to further complication
  2. rupture or ulceration of the surface which can result in cholesterol emboli, or provide a site for thrombosis
  3. thrombosis superimposed on the plaque, most often presents on a disrupted plaque
  4. hemorrhage into the plaque, form rupture of fibrous cap or capillaries into the plaque
  5. medial atrophy in advanced AS can lead to the formation of aneurysms

HYPERTENSION

Hypertension: prevalence about 25% overall, with incidence increasing with age.  African Americans are affected at 2x the rate of Caucasian Americans and also tend to suffer increased consequences and complications from HTN.  90-95% is idiopathic or essential HTN and the remainder is usually caused by renovascular HTN secondary to AS.  Cause is multifactorial and may include genetic factors (aldosterone metabolism or distal tubule sodium channel defects that cause increased sodium uptake), diet and salt intake, stress, smoking, and inactivity.

95% of HTN cases will be fairly stable and slowly progressing = benign HTN.  Malignant HTN occurs in about 5% of cases and rapidly progresses to renal failure, retinal hemorrhages and death if untreated.

BP depends on the cardiac output and TPR.  CO depends on blood volume, which is dependent on sodium.  TPR arises mainly from pressure in arterioles and is subject to control via vasoconstrictors and dilators.  Kidney regulates TPR via the renin-angiotensin pathway.  Angiotensin II both increases TPR via vasoconstriction and stimulates aldosterone secretion that increases blood volume.

Essential HTN arises from some disturbance in these mechanisms.  Two theories exist for possible pathogenesis:

  1. renal dysfunction leading to increased sodium retention despite normal arterial pressure.  This increases blood volume and consequently CO.  High CO causes peripheral vasoconstriction to prevent overperfusion of tissues.  With a higher TPR, the kidneys will excrete more sodium, and a new homeostasis gets established with a higher baseline BP.
  2. vasoconstriction and vascular hypertrophy precipitate increased TPR.  Heightened vasoconstriction may arise from stress, increased release of vasoconstrictors or increased vascular sensitivity to vasoconstrictors.  Angiotensin II also acts as a growth factor inducing SMC proliferation.  Vascular wall thickening appears to sometimes precede HTN.

HTN damages vessel walls, particularly in small arteries and arterioles.  In hyaline arteriolosclerosis, vessel walls are thickened with a homogenous pink layer that narrows the lumen, probably the result of leakage of plasma contents into the vessel wall and SMC response with increased connective tissue production.  Hyaline arteriolosclerosis may narrow vessel lumens and is associated with decreased perfusion and organ damage, particularly in the kidney.   Hyperplastic arteriolosclerosis is associated with acute HTN and shows up as onion-skin, concentric thickening of vessel walls with narrowed lumen.  There is increased production of basement membrane. May occur with a necrotizing arteriolitis, especially in the kidney.

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