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A. Introductionnavigator

  1. Components of Vessel Wall
    1. Intima - Endothelium
    2. Muscularis - Smooth Muscle Layers
    3. Adeventitia - fibrous connective tissue
  2. Functions of Blood Vessels
    1. Maintenance of vascular tone - changing blood vessel diameters
    2. In normal state, prevention of blood clotting
    3. In inflammatory state, permit leukocyte extravasation to affected site(s)
    4. In injured state, permit clot formation
  3. Normal Arterial Waveform
    [Figure] "Arterial Pressure Tracing"
    1. Wave tracing shown is derived from a normal peripheral artery
    2. Systolic upslope is rapid, and then falls as blood flow slows
    3. Dicrotic notch occurs because aorta distends in systole and compresses in diastole
    4. Therefore, aortic compression in diastole causes increase in blood pressure
    5. The waveform contains information about vessel compliance and impedance
    6. Alterations in the waveform correlate with vascular disease
  4. Vasoactive Compounds and Clotting Pathways
    1. Details of clotting systems are discussed elsewhere
    2. Many vasoactive molecules have direct effects on clotting pathways
    3. Tissue plasminogen activator levels inversely correlate with vascular disease
    4. Inflammatory cascade and acute reactants also interact with clotting pathways
  5. Endothelial Cells [30,35,55]
    1. Play a major role in all aspects of vascular biology
    2. Derived from multipotent CD34+ hemangioblastic progenitor cells [38]
    3. These cells also give rise to bone marrow hematpoietic cells
    4. Endothelial cells circulate as CD34+CD133+VEGFR2+ precursors
    5. New blood vessels express CD31 and lose CD34 expression
  6. Endothelium
    1. Total surface area in human adult is ~700 square meters (~1.5kg mass)
    2. Normal endothelium is antithrombotic, anti-inflammatory
    3. Production of vasodilator (nitric oxide) and vasoconstrictor (endothelin) substances
    4. Response to vasoactive substances
    5. Interaction with smooth muscle cells
    6. Interaction with leukocytes for migration into tissues
    7. Normal endothelium inhibits atherosclerotic plaque generation

B. Physiologic Regulation of Vessel Diameter navigator

  1. Blood Pressure and Vascular Resistance [8]
    1. Resistance is primarily determined arterioles and very small arteries
    2. Key interactions occur between endothelium and smooth muscle layers
    3. Compounds which regulate vascular diameter ("tone") are called vasoactive
    4. Vasoactive compounds are usually divided into vasoconstrictors and vasodilators
    5. Normal vascular control requires intact, healthy endothelium
    6. Shear stress (blood flow, viscosity, and vessel radius) can alter vessel diameter
    7. Reduced shear stress (reduced laminar blood flow) leads to vasoconstriction and can stimulate atherosclerotic plaque formation [36]
  2. Physiologic Vasodilators
    1. Heat
    2. Nitric Oxide (NO)
    3. Prostacyclin (PGI2)
    4. Adenosine
    5. Acetylcholine (weakly)
    6. Bradykinin (BK)
    7. Oxygen
    8. Shear Stress
    9. Substance P
    10. Natriurietic Peptides (ANP, BNP, calcium-activated neutral protease)
    11. Adrenomedullin
    12. Serotonin (under normal circumstances in most non-cranial vessels)
    13. Estrogen increases NO and prostacyclin, reduces endothelin 1 levels [2,28,33]
    14. Higher serum estrogen levels in men associated with reduced cardiovascular events [24]
    15. ß2-adrenergic receptors - modulated by polymorphisms in receptor [42]
    16. Many of these also block platelet activation (anti-thrombotic)
  3. Physiologic Vasoconstrictors
    1. Cold
    2. Angiotensin II
    3. Endothelins
    4. Thromboxanes
    5. Thrombin
    6. Adenosine Diphosphate (ADP)
    7. Vasopressin (Antidiuretic hormone, ADH)
    8. Platelet activating factor (PAF)
    9. Epinephrine / Norepinephrine - alpha adrenergic constriction > ß2-adrenergic dilation
    10. Serotonin - mainly in diseased (atheterosclerotic) vessels and in cranial vessels
    11. Nicotine and other components of cigarette smoke (see below)
    12. Urotensin II - potent arterial vasoconstrictor, associated with renal dysfunction [41] and congestive heart failure [50]
    13. High fat meals block endothelial dilation (see below)
    14. Many of these molecules also enhance platelet activation (pro-thrombotic)
  4. Membrane Potential [40]
    1. Endothelial cell membrane potential determines vasoactivity
    2. Normal resting membrane potential is -30 to -60 mV
    3. Hyperpolarized endothelium is resistant to vasoconstriction
    4. More positive membrane potentials lead to increases in intracellular calcium
    5. Calcium increases by release of intracellular stores and influx
    6. Potassium channels are the major regulators of voltage potential
    7. ATP sensitive, K(ATP), and calcium dependent, K(Ca), potassium channels are key
    8. Opening K(ATP) and K(Ca) channels lead to hyperpolarized membrane channels
  5. Smooth Muscle Contraction
    1. Calcium binds to calmoldulin and this complex activates myosin light chain kinase (MLK)
    2. MLK phosphorylates the regulatory light chain of myosin
    3. Myosin's ATPase is activated and myosin-actin crossbridges form
    4. This leads to vasoconstriction

C. Vasodilatorsnavigator

  1. Nitric Oxide (NO)
    1. Potent vasodilator, formerly called EDRF (endothelial derived relaxing factor)
    2. Synthesized from L-arginine (Arg) by nitric oxide synthetase (NOS)
    3. Three forms of NOS exist: constitutive NOS (cNOS), inducible (iNOS), and neural (nNOS)
    4. cNOS is normally present and active in endothelium (also called eNOS)
    5. iNOS is involved in inflammation and is highly upregulated in sepsis [60]
    6. nNOS is a neurotransmitter
    7. NO also inhibits platelet aggregation and smooth muscle proliferation
    8. IL1ß, IL6, TNFa, many other cytokines stimulate nitric oxide production [2]
    9. Nitric oxide activates K(ATP) and K(Ca) channels leading to hyperpolarized endothelium
    10. Hyperpolarized endothelium is insensitive to vasoconstrictors (see below)
    11. Oxidized LDL inhibit NO production
    12. Superoxide and other reactive oxygen species (ROS) combine with NO and inactivate it [52]
    13. Superoxide + nitric oxide form peroxynitrite radicals which are toxic to endothelium
    14. Endogenous NOS inhibitor is asymmetrical dimethylarginine (aDMA)
    15. aDMA levels are independent predictor of mortality in hemodialysis [46]
    16. aDMA levels are independent predictor of acute coronary events in non-smoking men [47]
  2. eNOS (cNOS) Alleles and Nitric Oxide Production
    1. eNOS gene is 21kb encoded on chromosome 7q35-36
    2. Many polymorphisms in eNOS associated with altered levels of NO production
    3. Promoter polymorphism T->C at -786 associated with reduced transcription
    4. T->C allele associated with increased coronary spasm and venous thromboembolism
    5. Exon 7 (Glu298->Asp), but not a promoter, polymorphism associated with systemic sclerosis
  3. Hemoglobin and Nitric Oxide [3]
    1. Hemoglobin (Hb) scavenges nitric oxide (NO) through high affinity Fe2+ binding sites
    2. The affinity of Hb for NO is ~8000 times that for O2
    3. Hb can carry NO through an S-nitrosothiol moiety
    4. O2 binding to Hb increases its affinity for NO
    5. NO release is enhanced in hypoxic tissue
    6. Since NO is a potent vasodilator, NO release in hypoxic tissue increases blood flow there
    7. Note that NO binding sites are essentially independent of O2 binding sites
  4. Bradykinin (BK) [8,43]
    1. Kinins are peptide mediators of acute and subacute inflammation
    2. Stimulate production of nitric oxide and vasodilatory prostaglandins
    3. Cause vasodilation, vascular leak, pain and neurotransmitter release
    4. BK is degraded by angiotensin converting enzyme, ACE (preferred substrate)
    5. BK interacts with the angiotensin system to conteract AT2 effects
    6. BK may be protective against development of left ventricular (LV) hypertrophy [44]
    7. Low expressor alleles of BK receptor (B2BKR) combined with ACE polymorphisms associated with specific levels of exercise induced LV hypertrophy [44]
    8. Increased levels of BK with ACE inhibitors (ACE-I) likely cause associated cough
    9. Also involved in angioedema due to ACE inhibitors or C1 inhibitor deficiency [54]
  5. Neutral Endpopeptidase (NEP) [39]
    1. NEP metabolizes endogenous vasodilator peptides
    2. These vasodilators included natriuretic eptides, adrenomedullin, and BK
    3. Therefore, inhibitors of NEP increase vasodilation
    4. Omapatrilat, a NEP inhibitor, may be superior to lisinopril in CHF [39]

D. Vasoconstrictors [40]navigator

  1. Major Vasoconstrictors [8]
    1. Norepinpherine (NE) - sympathetic nervous system
    2. Angiotensin II (AT2) - part of renin-angiotensin-aldosterone system
    3. Vasopressin (ADH) - stimulated by AT2
    4. Endothelin
    5. Aldosterone (stimulated by AT2) probably also plays a role
  2. NE
    1. Mediates its effects through alpha-adrenergic receptors
    2. Membrane depolarization opens voltage-gated calcium channels
    3. Calcium influx is required for vasoconstriction
    4. Activation of K(ATP) channels by NO blocks NE mediated vasoconstriction
  3. AT2 [48]
    1. AT2 converted from angiotensin I (AT1) by angiotensin converting enzyme (ACE)
    2. AT1 is derived from angiotensinogen by renin
    3. ACE is also a BK catabolizing enzyme (bradykininase, see above)
    4. AT2 is an extremely potent vasoconstricting hormone
    5. AT2 also stimulates production of aldosterone from the adrenal gland
    6. AT2 increases oxidative stress in vasculature and target organs
    7. Increased oxidative stress (reactive oxygen species, ROS) adversely affect endothelium
    8. ROS combine with nitric oxide (NO) and block induced endothelial dilation [52]
    9. Peroxynitrite formed from ROS+NO is also directly toxic to endothelium
    10. Thus, HTN, direct AT2 effects, and NO reduction cause vascular dysfunction
    11. Interleukin 6 (IL6) and nuclear factor kappa B (NF-kB) increased by AT2
    12. Oxidative stress also increases transforming growth factor ß (TGFß) levels
    13. IL6 stimulates monocyte chemotactic protein 1 which is proinflammatory
    14. AT2 directly stimulates plasminogen activator inhibitor (PAI)-1 which is prothrombotic
    15. These effects lead to endothelial damage and enhance atherosclerotic damage
    16. Prothrombotic and proinflammatory effects may also increase acute coronary events
    17. Chronically elevated levels of AT2 may lead to HTN, coronary artery disease [48]
  4. Vasopressin (Antidiuretic Hormone, ADH) [40,60]
    1. Main action of ADH is to reduce water loss through the kidney
    2. This occurs at serum ADH levels of 1-7pg/mL
    3. ADH also has vasoconstricting activity at much higher levels (10-200pg/mL)
    4. Pharmacologic administration of vasopressin in the 150-200pg/mL produces good pressor responses, even in vasoconstrictor resistant states such as sepsis [60]
  5. Endothelin [10,31]
    1. Potent vasoconstricting compounds, made by endothelium, lung, brain, kidney
    2. Three closely related endothelins encoded on different chromosomes
    3. Angiotensin II, shear stress, TFGß, and Interleukin 1 stimulate endothelin production
    4. Levels increased with reduced cardiac output as in heart failure (CHF) [2]
    5. Two receptors - ETa and ETb found in vascular smooth muscle, both mediate constriction
    6. Bosentan (Tracleer®) is an orally active, mixed ETa/ETb receptor antagonist [12]
    7. Administration of 100-2000mg/day bosentan reduces blood pressure (~12mm max)
    8. Bosentan increased plasma endothelin, mild reduction in AT2
    9. As effective as enalapril in patients with systemic HTN but side effects prevent use
    10. Bosentan 62.5-125mg po bid reduced pulmonary pressures and improved functional class in patients with severe, symptomatic pulmonary HTN [45]
    11. Bosentan caused headache, flushing, leg edema, some transaminase increases
    12. Bosentan is now FDA approved for pulmonary HTN with Class III/IV symptoms
    13. Additional endothelin blockers in development for HTN and renal protection [31]

E. Pathophysiologic Regulation of Vessel Diameter [8] navigator

  1. Effects of Smoking
    1. Smokers have abnormal arterial waveforms [4]
    2. Impairs endothelial dependent vascular relaxation (Whites > Chinese) [5]
    3. Hb binds carbon monoxide and this can alter NO binding and O2 binding
    4. Smoking is synergistic with cocaine in induction of coronary vasocontriction
  2. High Fat Meals and Endothelium [7]
    1. Saturated fats are associated with endothelial dysfunction
    2. Obth acute and chronic effects have been observed
    3. Single high fat meal blocks arterial vasodilation for 2-4 hours
    4. Triglyceride level increases correlated best with inhibition of vasodilation
    5. Vitamins E (800 IU) and C (1gm) given prior to high fat meal reversed inhibition
    6. Data strongly suggest that anti-oxidant vitamins can prevent acute effects of high fat meals and possibly that patients would benefit from prophylaxis
  3. Cocaine induces diffuse vasocontriction [9]
  4. Homocysteine [49]
    1. Inhibits endothelial cell mediated vasodilation
    2. Folate supplementation reduces homocysteine levels and improves vasodilation

F. New Vessel Formation [13,17]navigator

  1. Definitions
    1. Angiogenesis: extension of already formed primitive vasculature by sprouting new capillaries through migration and proliferation of previously formed endothelial cells
    2. Vasculogenesis: process of in situ formation of blood vessels from endothelial progenitor cells (angioblasts)
    3. Arteriogenesis: increase in size and diameter of existing arteriolar connections by remodeling
  2. Blood vessel formation is critical to:
    1. Embryogenesis: organ formation
    2. Wound healing
    3. Hypoxia response (organ hypertrophy, vessel damage, vessel occlusion)
    4. Response to hypoxia is one of strongest drivers of angiogenesis [57]
    5. Growth of malignancies
    6. Pannus formation in synovium of rheumatoid arthritis patients requires angiogenesis
  3. Endothelial cells derived from bone marrow CD34+ stem cells and express CD31 [53]
  4. Known Angiogenic Proteins
    1. Vascular endothelial growth factor (VEGF; family of ~45K glycoproteins)
    2. Fibroblast Growth Factor (FGF) - alpha (acidic, 16.4K) and beta (basic, 18K) [51]
    3. Angiopoietin-1 - maturation and maintenance of vascular system
    4. Angiogenin (14K)
    5. Transforming Growth Factor (TGF) - alpha (5.5K) and beta (25K)
    6. Platelet derived growth factor (PGDF; 45K)
    7. Granulocyte colony stimulating factor (G-CSF; 17K)
    8. Placental growth factor (25K) - homologous to VEGF family members
    9. Interleukin 8 (IL-8; 40K)
    10. Tumor Necrosis Factor (TNF) alpha (17K)
    11. Hepatocyte growth factor (HGF, 92K)
    12. Proliferin (35K)
  5. Hypoxia Driven Angiogenesis [57]
    1. Hypoxia stimulates the expression of hypoxia inducible factor (HIF-1)
    2. HIF-1 mRNA is induced by ischemia and infarction in many situations
    3. HIF-1 mRNA also induced by epidermal growth factor, AKT activation
    4. HIF-1 is a transcription factor composed of alpha and beta chains
    5. HIF-1 response elements found in several angiogenesis associated genes (above)
    6. VEGF and VEGF receptor are both induced by HIF-1
    7. Insulin like growth factor (IGF) 2 and IGF binding proteins -1, -2, -3 all induced
    8. Promoting angiogenesis in ischemic diseases is potential new therapeutic modality [17]
  6. VEGF [13,37,56]
    1. Very important family of growth factors for development of new vessels
    2. Family Members: VEGF-1 (-A), -2 (-C), -3 (-B), VEGF-D, VEGF-E
    3. Overexpression implicated in many diseases, particularly ischemic conditions
    4. HIF-1 stimulates VEGF mRNA expression
    5. Inhibition of VEGF being investigated in neovascular and neoplastic diseases (see below)
    6. Local expression of increased VEFG expression for treatment of ischemic diseases
    7. Gene-transfer mediated expression of VEGF can induce collateral vessel formation [56]
  7. Integrin alpha-v beta-3
    1. Essential to angiogenesis process
    2. Independent of mitogenic cytokine inducer
    3. Integrin expressed on activated endothelial cells
    4. Cytoplasmic domain of integrin interacts with cytoskeletal components
    5. Inhibition of alpha v beta 3 integrin blocks neo-angiogenesis
  8. Non-Neoplastic Angiogenic Diseases
    1. Ocular neovascularization - proliferative retinopathy (diabetes), macular degeneration
    2. Psoriasis - hypervascular skin lesions
    3. Hemangiomas - usually in children
    4. Developmental Disorders - bowel atresia, vascular malformations, facial atrophy
  9. Tumor Angiogenesis [17]
    1. New blood vessel growth (angiogenesis) is essential to tumor growth
    2. Tumors secrete a variety of angiogenic factors including TGFß [58]
    3. Local endothelial cells are activated and express integrin alpha v beta 3 (aVß3)
    4. Vascular endothelial growth factor (VEGF) is also believed to play a major role [59]
    5. Neovascularized tumors can then grow
    6. Bevacizumab (Avastin®) anti-VEGF monoclonal Ab approved for first line colon cancer
    7. A number of anti-VEGF receptor Abs are in clinical trials in cancer
  10. Hemangioma
    1. Abnormal angiogenesis usually with high levels of urinary beta FGF
    2. Occurs in ~1% of neonates (up to 20% of low birthweight premature infants)
    3. Often grow rapidly in first year of life and slow down during next 5 years
    4. Most hemangiomas have regressed by age 15
    5. Occasionally (~10%), these tumors can cause serious tissue damage
    6. Sight, organ function, others, may be at risk
    7. Juvenile capillary hemangiomas of the stomach may lead to hematemesis [34]
    8. ~30% of severe hemangiomas respond to glucocorticoids
    9. Interferon alpha-2a appears to accelerate regression in >90% of hemangiomas
  11. Local expression of growth factors via gene transfer is being investigated for occlusive vascular (ischemic) disease [13]
  12. Angiogenesis is defective in systemic sclerosis, with reduced and abnormal endothelial precursors [6]

G. Endogenous Inhibitors of Angiogenesis [57]navigator

  1. Angiostatin
  2. Brain angiogenesis inhibitor 1
  3. Endostatin
  4. Glioma derived angiogenesis inhibitor factor
  5. Interferons alpha and gamma
  6. Interleukins -12 and -18
  7. Maspin
  8. Platelet factor 4
  9. Prolactin fragement 16K
  10. Thrombospondin 1
  11. Vascular endothelial growth inhibitor
  12. Vasostatin

H. Atherosclerosis [14,15,30,36] navigator

  1. Pathology
    1. Deposits of cholesterol, macrophages, foam cells in subendothelial region
    2. These deposits are called "plaques" or atherosclerotic plaques
    3. The plaques contain oxidized low density lipoprotein (LDL) and other components
    4. Macrophages laden with lipids, often called "foamy histiocytes", are prominant
    5. Platelet products and fibrin, particularly in "young" plaques
  2. Endothelial damage and dysfunction from various causes is central to atherosclerosis [35]
    1. Reactive oxygen species (ROS) affect endothelium directly and through cholesterol
    2. Oxidized LDL is toxic to vascular cells
    3. Lp(a), a form of LDL has homology to plasminogen and causes a prothrombotic state
    4. May cause chronic irritation and inflammation of blood vessel wall
    5. Triglycerides and other fats also have acute effects on endothelium [7]
    6. Macrophages are recruited to the area to aide in healing the damaged endothelium
    7. The macrophages often express activation markers and secrete cytokines
    8. T cells are only found in early lesions, and appear to initiate macrophage activation
    9. Reduction of LDL chol to ~100mg/dL or less reduces endothelial dysfunction
    10. Antioxidant vitamins may inhibit LDL oxidation [16]
    11. Reduced shear stress (reduced laminar blood flow) stimulates plaque formation [36]
  3. Young plaques are unstable, predisposed to rupture [18]
    1. Plaque rupture leads to exposure of Tissue Factor (TF or Clotting Factor III)
    2. TF exposure stimulates extrinsic clotting pathway
  4. Older plaques are more stable and show endothelial erosion (rather than rupture) [19]
    1. Often asymptomatic, but contribute to large thrombus formation in ~25% of cases
    2. Gradual increase in size of plaques leads to symptoms unless collateral vessels present
    3. Minimal lumen diameter is a good predictor of chronic events (e.g. stable angina)
    4. Intimal to medial ratio can be determined with ultrasound as well as histologically
  5. Factors which reduce plaque growth
    1. Reduction in cholesterol levels (even if normal) - primary and secondary prevention [23]
    2. Anti-inflammatory agents - increasing evidence for efficacy of aspirin
    3. Elevated HDL Levels
    4. Nitric oxide production by endothelial cells inhibits plaque growth
    5. Estrogen replacement increases nitric oxide and reduces endothelin action [2]
    6. Vitamin E may inhibit plaque growth as well
    7. Combined vitamins C + E block acute effects of homocysteine on vasculature [32]
    8. Nitric oxide precursor arginine also blocks vascular effects of homocysteine [32]
    9. Folate, Vit B6 and B12 reduce homocysteine levels
    10. Folate supplementation improves endothelial cell mediated vasodilation [49]
  6. Cardiovascular Disease (CVD) Risk Factors
    1. All of the following increase plaque growth:
    2. Hypertension
    3. Diabetes Mellitus
    4. Elevated serum total and/or LDL cholesterols
    5. Smoking
    6. Elevated plasma homocysteine levels [20]
    7. Reduced serum HDL cholesterol levels
    8. Generalized vascular inflammation [21]
    9. Localized vascular infections [22]
    10. Insulin resistance [29]
    11. Genetic contributions

Resources navigator

calcMean Arterial Pressure (MAP)

References navigator

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