Vascular Diseases: Structure and Function

• Vascular diseases are significant in medicine since they cause common and lethal conditions. Most significant vascular diseases arise as a result of arterial lesions, and venous disorders may also inflict substantial harm. Vascular diseases are caused by the narrowing or obstruction of vessel lumens and/or weakening of vessel walls, causing dilation and rupture.

Structure and Function of Blood Vessels

• All blood vessels have a tube-like structure with an endothelial cell lining, surrounded by varying quantities of smooth muscle cells and extracellular matrix (ECM). The structure of each component varies based on functional needs.
• Arterial walls are thicker than veins with reinforcing layers of smooth muscle cells, to accommodate pulsatile flow and higher blood pressures.
• As arteries narrow to arterioles, the ratio of wall thickness to lumen diameter increases, allowing better regulation of intravascular pressures. Veins are distensible, thin-walled vessels with high capacitance.
• Atherosclerosis mainly occurs in larger, muscular arteries, while hypertension affects small arterioles, and certain vasculitis forms affect vessels of a certain caliber.
• Vessel walls have three concentric layers: intima, media, and adventitia, which are most apparent in larger vessels and especially arteries.
• The intima consists of an endothelial cell monolayer on a basement membrane with minimal underlying ECM then separated by an internal elastic lamina.
• The media is composed of smooth muscle cells and ECM, surrounded by loose connective tissue, nerve fibers, and smaller vessels of the adventitia.
• An external elastic lamina exists in some arteries and defines the transition between media and adventitia.
• Diffusion meets the nutritional needs in thin-walled vessels, but small arterioles (vasa vasorum) in the adventitia are responsible for nutrient supply to the outer half to two-thirds of the media in medium and large vessels.

Types of Arteries

• Large elastic arteries (aorta, arch vessels, iliac and pulmonary arteries) have elastic fibers alternating with smooth muscle cells throughout the media, expanding during systole and recoiling during diastole. Elasticity loss leads to "stiff pipes" that transmit high arterial pressures or dilated, rupture-prone conduits.
• Medium-sized muscular arteries (coronary and renal arteries) primarily have smooth muscle cells in the media, with elastin limited to the internal and external elastic lamina. Contraction (vasoconstriction) and relaxation (vasodilation), controlled by the autonomic nervous system and local factors, regulate regional blood flow.
• Small arteries (2 mm or less) and arterioles (20 to 100 µm) reside in connective tissue. Resistance of blood flow is most regulated by the media in these vessels composed of smooth muscle cells.
• Arterioles modulate blood flow resistance is regulated. Pressures decrease the velocity of blood flow sharply decrease as pressure drops through arterioles, which becomes steady. Diminished arteriolar lumen size markedly effects blood pressure (resistance is inversely proportional to the fourth power of the diameter).
• Capillaries, with lumen diameters similar to red cells (7 to 8 µm), are lined by endothelial cells and pericytes. They have high total cross-sectional area with a low blood flow rate, hence thin walls and slow flow makes them ideal to diffuse substances between blood and tissue.
• Capillary networks must be very rich. Metabolically active tissues such as the heart has the highest density because diffusion of oxygen and nutrients isn't efficient beyond 100 µm.
• Veins receive blood from the capillary beds as postcapillary venules, which anastomose to form collecting venules and progressively larger veins. Vascular leakage (edema) and leukocyte emigration occurs in postcapillary venules.
• Veins have larger diameters, lumina, thinner walls, are prone to dilation, compression, and penetration more than arteries at the same level of branching. Veins also prevent backflow by having valves.
• The venous system contains roughly 2/3 of the blood and has a substantial capacity.
• Lymphatics are thin-walled, endothelium-lined channels remove fluid (lymph) from the interstitium of tissues, it returns to the blood via the thoracic duct. Lymph contains mononuclear inflammatory cells and proteins. Lymphatics are also channels that enable constant monitoring of the peripheral tissues, it disseminating diseases such as tumor cells to distant locations.

Endothelial Cells

• Endothelium, a continuous sheet of cells lining the entire vascular tree, regulates blood and vessel function.
• Resting endothelial cells maintain a nonthrombogenic blood-tissue interface, adjust inflammation, and affect growth of other cell types. They influence vasoreactivity by producing relaxing (nitric oxide) and contracting (endothelin) factors.
• The interendothelial junctions are normally impermeable but can open due to hemodynamic stress and vasoactive agents, flooding adjacent tissues with electrolytes and protein.
• Vacuolar transcytosis and endothelial cells allow movement of solutes in inflammatory cell recruitment.
• Endothelial cells show phenotypic variability depending on the anatomic site and adaptations to local cues, displaying distinct transcriptional programs and behaviors (large vessels versus capillaries, arteries versus veins). Fenestrations are specializations that facilitate filtration.
• Conversely, in the central nervous system, endothelial cells generate an impermeable blood-brain barrier.
• Maintenance of nonthrombogenic endothelium requires laminar flow, growth factors (VEGF), and basement membrane adhesion. Trauma understandably causes thrombosis and vasoconstriction on vessel walls.
• Endothelial cells respond to physiological and pathological stimuli by modulating their usual functions and undergoing endothelial activation with new properties.
• Inducers of endothelial activation include bacterial products, inflammatory cytokines, hemodynamic stresses, lipid products.
• Activated cells undergo shape changes, expressing adhesion molecules, and produce cytokines, chemokines, growth factors, pro- and anticoagulant factors. These responses are intended to respond to the original stimulus, some are rapid while others take time. Exposure to inducers of activation can lead to endothelial dysfunction, resulting in hypercoagulable states, and increased oxygen free radical production, as well as thrombosis, atherosclerosis, or formation of vascular lesions of hypertension and diabetes.

Vascular Smooth Muscle Cells

• Smooth muscle cells participate in normal repair and pathologic processes (atherosclerosis). Stimulated cells proliferate, upregulate ECM collagen, elastin, proteoglycan production, and elaborate growth factors and cytokines, mediating vasoconstriction or vasodilation.
• Migratory and proliferative activities are regulated by numerous factors (platelet-derived growth factor (PDGF), endothelin, thrombin, fibroblast growth factors, interferon-y (IFN-γ) and interleukin-1 (IL-1).
• Quiescent state is maintained by heparan sulfate, NO, and transforming growth factor-a (TGF-a).

Congenital Anomalies

• Uncommon vascular supply variations can be difficult during surgery/cardiac interventions. Three anomalies:
• Berry aneurysms are thin-walled arterial outpouchings in cerebral vessels, usually around the circle of Willis. These occur where arterial media is congenitally attenuated and can rupture, causing intracerebral hemorrhage.
• Arteriovenous (AV) fistulas are abnormal connections between arteries and veins without an intervening capillary bed, can be developmental defects, rupture of arterial aneurysms into adjacent veins, injuries piercing arteries and veins, or inflammatory necrosis of adjacent vessels. AV fistulas can be created surgically for hemodialysis.
• Extensive AV fistulas may produce high-output cardiac failure, it circulates large volumes of blood from the arterial to venous circulation.
• Fibromuscular dysplasia causes thickening due to medial/intimal hyperplasia and fibrosis, predominantly in young women. Focal wall thickening leads to stenosis alongside frequent abnormal vessel spasm. In the renal arteries, renovascular hypertension happens. Wall thickening results in medial attenuation + vascular outpouchings can occur.

Blood Pressure Regulation

• Systemic and local blood pressure must be maintained to prevent adverse outcomes with cardiac output and peripheral vascular resistance. Low blood pressure causes inadequate organ perfusion, which causes issues with organ function. Hypertension causes vessel and end-organ damage and major risk factors for atherosclerosis.
• CO (cardiac output) is a function of stroke volume and heart rate while stroke volume reflects filling pressure, which is regulated via sodium homeostasis. Heart rate and myocardial contractility are regulated by adrenergic systems.
• Peripheral resistance is often regulated at the level of the arterioles. Vascular tone involves a balance between vasoconstrictors (angiotensin II, catecholamines, endothelin) and vasodilators (kinins, prostaglandins, NO). Resistance vessels auto-regulate and elevated blood flow triggers vasoconstriction. Blood pressure is fine-tuned by tissue pH and hypoxia to meet metabolic demands.
• Kidneys, adrenals, and myocardium interact to affect vascular tone and blood volume, by sodium balance. Kidneys regulate peripheral resistance and sodium excretion via the renin-angiotensin systen.
• Renin is released in response to low blood pressure, elevated catecholamines, or low sodium levels. This is a proteolytic enzyme produced by juxtaglomerular cells.
• Renin cleaves angiotensinogen to angiotensin I, which is converted to angiotensin II by ACE. Angiotensin II raises blood pressure by vasoconstriction, stimulating aldosterone secretion, and increasing tubular sodium resorption.
• The kidney produces vascular relaxing substances (prostaglandins and NO) counterbalance the vasopressor effects of angiotensin.
• Aldosterone increases blood pressure by increasing sodium resorption and water, causing potassium excretion.
• Myocardial natriuretic peptides inhibit sodium resorption which causes vasodilation in response to an increase in volume.

Hypertensive Vascular Disease

• Hypertension is a major health problem. It is often asymptomatic for years.
• Besides increasing the risk of stroke/coronary disease, hypertension causes cardiac hypertrophy/heart failure, aortic dissection, multi-infarct dementia, and renal failure. Genetic and environmental factors leads to essential hypertension by increasing blood volume and/or peripheral resistance.
• Sustained diastolic pressures >90 mm Hg or systolic pressures >140 mm Hg indicate increased risk of atherosclerosis and are cutoffs to diagnose hypertension. About 25% of the general people are hypertensive.
• Risk is higher in African Americans and those with cardiovascular risk factors.
• High reduction pressure dramatically reduces all forms of related hypertension.
• About 5% of hypertensive patients have rapidly accelerating blood pressure, that's rapidly death. Malignant hypertension includes systolic pressures that are over 200 mm Hg or diastolic pressures that are over 120 mm Hg, renal failure, and hemorrhages, which can occur either de novo, or pre existing benign hypertension.

Vascular Wall Response to Injury

• A wide spectrum of vascular conditions, injury causes endothelial cell that include biochemical, immunological, or hemodynamic damages.
• Integrated function gives the vasculature a response towards stimuli. Endothelial dysfunction leads to thrombosis, atherosclerosis, and hypertensive vascular lesions. Smooth muscle cell proliferation and matrix synthesis help with vessel wall repair, but can cause luminal occlusion.
• Loss of endothelial cells stimulates smooth muscle cell growth and the start of matrix synthesis. Healing will involve migration of smooth muscle cells or precursor cells into the intima. ECM is then synthesized forming a neointima with an intact endothelial cell layer. Triggers neointimal causes include trauma, hypertension, toxic exposure, or dysfunction, forming the stereotypical response.
• Neointimal smooth muscle cells divide, synthesize, and lack the contracting medial capacity and are synthesized growth factors and cytokines.
• Restoration and/or normalization causes intimal smooth and nonproliferative cells. Continued insults will cause stenosis. Intimal thickening part of aging.

Arteriosclerosis

• Arteriosclerosis is the hardening or thickening in arterial walls, that will reflect arterial wall thickening which will lose elasticity. Three distinct types that have different clinical and pathologic conseqences:
• Arteriolosclerosis affects downstream arteries which causes ischemic injury. There are hyaline and hyperplastic arteriolosclerosis for reference with hypertension.
• Mönckeberg medial sclerosis causes calcific deposits within those in 50, that dont affect vessel.
• Atherosclerosis, from, often causes thickening on arterial walls.

Atherosclerosis

• Characterized by atheromas (or atherosclerotic plaques).
• Atheromatous plaques which are composed of lipid cores covered by fibrous caps will cause mechanical obstruction which can also lead to rupturing the thrombosis of vessel. Plaques weaken underlying media, leading to aneurysm creation. The mortality rates are extremely high with approximately half of all deaths associated to this.

Epidemiology of Atherosclerosis

• Atherosclerosis is ubiquitous and most commonly found in western countries. It is five times higher in the US compared to Japan.
• Japanese people immigrants also have the same risk once adopted.
• Risk is correlated through multiple factor studies, some are controllable and modifiable. Two factors increase the risk to four, three will increase the risk to seven.
• Familial history will cause risk with those, or polygenic traits.
• Silent Lesions are caused, then it is clinically until threshold, it has five fold change between 40 and 60. Death rate continues up.
• Premenopausal are protected, which complications are also uncommon. Incident in atherosclerosis causes with greater incidence of those, no benefit and will continue to increase risk if estrogen hormonal therapy.

Modifiable Major Risk Factors

• Hyperlipidemia-and, more specifically, hypercholesterolemia is a major factor for development, increased risk with low-density lipoprotein (LDL) cholesterol.
• By contrast, high-density lipoprotein (HDL) which mobilized cholesterol from developing and existing vascular plaques for liver excretion, those correlated with minimal risk.
• Dietary and pharmacologic interventions, serum cholesterol are reduced with a High dietary intake of cholesterol and saturated fats (present in egg yolks, animal fats, and butter, for example) raises plasma cholesterol levels. Conversely, diets low in cholesterol, and/or containing higher ratios of polyunsaturated fats, lower plasma cholesterol levels. a Omega-3 fatty acids (abundant in fish oils) are beneficial, whereas (trans)-unsaturated fats produced by artificial hydrogenation of polyunsaturated oils (used in baked goods and margarine) adversely affect cholesterol profiles. a Exercise and moderate consumption of ethanol raise HDL levels, whereas obesity and smoking lower them. a Statins widely used class of drugs lower circulating cholesterol levels inhibit coenzyme a.
• Hypertension increases risk the development of those with, hypertension will increase IHD.
• Smoking increases in women. Which doubles relation to IHD mortality.
• Diabetes mellitus with raised cholesterol is linked to it as well. Other factors equal with the incident the disorder increased threefold with those. It includes stroke and is a 100 fold on an atherosclerosis.

Additional Risk Factors

• Roughly 20% are from those with less than identifiable risk factors, for example LDL. Some factors that contribute.
• Inflammation is what happens at every stage of Atheromatous Plaque and the risk will become stratification of the inflammatory cells. The markers correlated towards those as C protein.

CRP levels

• CRP, a member of family synthesized cells in response to a variety of cytokine. Secretion activate atherosclerotic cell. Levels are at risk value of myocardial,stroke which is also linked to cardiovascular. The levels are high and direct that exercise lowers. They reduce levels those, and their LDL will suggest also anti.

Hyperhomocysteinemia

• Serum homocysteine levels also correlated, the stroke and venous, Homocystinuria elevated, is vascular. Although low may be effected it remains the B in supplemental affects.

Metabolic Syndrome

• It is central is this which insulin resistance and hypertension caused from adipocytes. The dyslipidemia, hyperglycemia, hypertension are all a factor that may endothelial damage.

Lipoporotein

• Is LDL with apolipoprotein, levels are and will have risk for disease.

Levels that will cause major risk for events.

• Activation which will cause activated receptors which is atherogenic.
• Difficult factors which also exercise and stressors.

Clinical Consequences

• Large, medium, elastic and arteries mostly affected by atherosclerosis and ischemia. Includes brain, lungs, heart disease. Consequences are attack, and arteries on vascular extremities.
• History will depend on stability for the plaque.
• Smaller compromises perfusion.
• Plaque lead to vascular catastrophies and will then also lead to thrombus which will embolized.
• Vessel aneurysm will cause formation that will then lead to formation.

Atherosclerotic Stenosis

• Remodeling tends to preserve lumial via increasing. Therefor expands. This the limit of the flow. Critical point in blood, and cardiac will occur at fixed at 70 percent. Patients will suffer in chest.
• The toll will then cause the arteries to have disease that will ischemia.

Plaque Change

• Erosion is plaque that will then occur for vascular. The following plaque ruptures are in three groups. -Rupture causing constituents.
• Exposing underlying basal membrane. -Hemorrhade within extending volume.

Certain types of plaques believed as high risk for rupturing, are thin. With low smooth, These caps are referred as weaker. Continuous remodeling.