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Vascular events – The vessels which show this are arterioles, capillaries and venules.

1. Vasoconstriction
   • First event
   • Transient event (lasting for few seconds)
   • Reflex
2. Vasodilation
   • Increased Redness (Rubor)
   • Increased Temperature (Calor)
   • Mediators of the event are Histamine & Serotonin
3. Increased Vascular Permeability
   • Every blood vessel is lined by endothelial cells. They are positive for CD 34. The fluids (Plasma, plasma proteins, WBCs) exudate, which results in Swelling (Tumor)
4. Stasis
   • When plasma comes out from blood vessels, the RBCs become concentrated. In other words, Viscosity is increased
   • This results in sluggish blood flow

Hallmark event of Acute Inflammation Increased Vascular Permeability (most commonly seen in Post Capillary Venules)

What are vascular events of inflammation?

Introduction – Inflammation is a ubiquitous, integrated and complex response to insults by pathogens, immunologically-mediated stimuli, irritants or chemicals. Inflammation, however, may also contribute to tissue damage if excessive or chronic. The vascular system is key to the inflammatory response since most components of the inflammatory response transit through the blood and vessels.

1. In the vascular system, acute and chronic inflammation lead to endothelial dysfunction and arterial remodelling, which underlie many cardiovascular diseases.
2. Vascular inflammation is a common response to injury and involves many cell types (immune cells, vascular smooth muscle cells (VSMC), perivascular adipocytes and fibroblasts), numerous mediators (cytokines, chemokines and reactive oxygen species (ROS)), multiple receptors (toll-like receptors, receptor for advanced glycation end-products, tumour necrosis factor (TNF)α receptor-associated factors, NOD-like receptors, transforming growth factor-β-(TGF-β) activated kinase 1, cytokine and chemokine receptors) and complex pro-inflammatory signalling pathways (e.g., nuclear factor κB, mitogen-activated protein kinases, canonical wingless-related integration site (WNT)/β-catenin and Signal transducer and activator of transcription 3, STAT3).

Prolonged inflammation causes DNA damage, first step to vascular injury. At the core of many of these processes is an increased production of ROS, especially superoxide anions (O 2 – ) and hydrogen peroxide (H 2 O 2 ) and activation of injurious redox-sensitive signalling pathways,

1. In the present review, we propose a general overview of the basic mechanisms by which inflammation can alter arterial physiology and lead to vascular complications such as atherosclerosis and arterial stiffening.
2. We further aim to demonstrate the bidirectional association between inflammation and vascular diseases, i.e.

vascular consequences of primarily inflammatory diseases, and systemic disease caused primarily by inflammatory vascular disease. Finally, we review the epidemiological evidence of the association between low-grade chronic inflammation and vascular diseases and we will also expose to what extent ant-iinflammatory drugs can reverse the effects of inflammation on large vessels.

What are the vascular changes in acute inflammation?

Vascular Phase – In the vascular phase, small blood vessels adjacent to the injury dilate ( vasodilatation ) and blood flow to the area increases. The endothelial cells initially swell, then contract to increase the space between them, thereby increasing the permeability of the vascular barrier.

This process is regulated by chemical mediators (see Appendix). Exudation of fluid leads to a net loss of fluid from the vascular space into the interstitial space, resulting in oedema (tumour). The fluid present is termed an ” exudate “, and characteristically is high in protein contents due to the increased vascular permeability The formation of increased tissue fluid acts as a medium for which inflammatory proteins (such as complement and immunoglobulins) can migrate through.

It may also help to remove pathogens and cell debris in the area through lymphatic drainage.

What two vascular events occur in acute inflammation?

Seen here is vasodilation with exudation that has led to an outpouring of fluid with fibrin into the alveolar spaces, along with PMN’s. The series of events in the process of inflammation are:

Vasodilation: leads to greater blood flow to the area of inflammation, resulting in redness and heat. Vascular permeability: endothelial cells become “leaky” from either direct endothelial cell injury or via chemical mediators. Exudation: fluid, proteins, red blood cells, and white blood cells escape from the intravascular space as a result of increased osmotic pressure extravascularly and increased hydrostatic pressure intravascularly Vascular stasis: slowing of the blood in the bloodstream with vasodilation and fluid exudation to allow chemical mediators and inflammatory cells to collect and respond to the stimulus.

What are major vascular events?

We primarily focused on major vascular events, ie, nonfatal stroke, myocardial infarction, and vascular death, because these affect health status most and are the focus of intervention studies.

Does inflammation cause vasodilation or vasoconstriction?

Acute Inflammation – An early, if not immediate, response to tissue injury is acute inflammation. Immediately following an injury, vasoconstriction of blood vessels will occur to minimize blood loss. The amount of vasoconstriction is related to the amount of vascular injury, but it is usually brief.

• Vasoconstriction is followed by vasodilation and increased vascular permeability, as a direct result of the release of histamine from resident mast cells.
• Increased blood flow and vascular permeability can dilute toxins and bacterial products at the site of injury or infection.
• They also contribute to the five observable signs associated with the inflammatory response: erythema (redness), edema (swelling), heat, pain, and altered function.

Vasodilation and increased vascular permeability are also associated with an influx of phagocytes at the site of injury and/or infection. This can enhance the inflammatory response because phagocytes may release proinflammatory chemicals when they are activated by cellular distress signals released from damaged cells, by PAMPs, or by opsonins on the surface of pathogens. Figure \(\PageIndex \): (a) Mast cells detect injury to nearby cells and release histamine, initiating an inflammatory response. (b) Histamine increases blood flow to the wound site, and increased vascular permeability allows fluid, proteins, phagocytes, and other immune cells to enter infected tissue.

1. These events result in the swelling and reddening of the injured site, and the increased blood flow to the injured site causes it to feel warm.
2. Inflammation is also associated with pain due to these events stimulating nerve pain receptors in the tissue.
3. The interaction of phagocyte PRRs with cellular distress signals and PAMPs and opsonins on the surface of pathogens leads to the release of more proinflammatory chemicals, enhancing the inflammatory response.

During the period of inflammation, the release of bradykinin causes capillaries to remain dilated, flooding tissues with fluids and leading to edema. Increasing numbers of neutrophils are recruited to the area to fight pathogens. As the fight rages on, pus forms from the accumulation of neutrophils, dead cells, tissue fluids, and lymph.

What causes vascular permeability in acute inflammation?

Acute vascular hyperpermeability (AVH) – A rapid increase in vascular permeability occurs when the microvasculature is exposed acutely to any of a number of vascular permeabilizing factors, e.g., VEGF-A, histamine, serotonin, PAF, etc. Some of these agents (e.g., histamine, serotonin, VEGF-A) are normally stored in tissue mast cells and so may be released by agents that cause mast cell degranulation, e.g., allergy, insect bites, etc.

Single exposure to any of these permeability factors results in a rapid but self-limited (complete by 20–30 min) influx of plasma into the tissues. Not only is the quantity of extravasated fluid greatly increased above that found in BVP but its composition is greatly changed. As already noted, the fluid passing from the circulation into normal tissues under basal conditions is a plasma filtrate, i.e., a fluid consisting largely of water and small solutes but containing very little plasma protein.

However, the fluid that extravasates in AVH is rich in plasma proteins, approaching the levels found in plasma, and is referred to as an exudate, Among the plasma proteins that extravasate are fibrinogen and various members of the blood clotting cascade.

When these come into contact with tissue factor, a protein that is normally expressed by many interstitial cells, the clotting system is activated and the exudate clots to deposit fibrin, Fibrin forms a gel that traps water and other solutes, restraining their clearance by lymphatics or capillaries and resulting in tissue swelling (edema).

Fibrin in tissues has other functions that are discussed below. However, as long as the permeability stimulus is not continuous, the deposited fibrin is rapidly degraded without further consequences. AVH also differs from BVP in that, as Guido Majno demonstrated, the vascular leakage takes place not from capillaries but from post-capillary venules, highly specific vessels just downstream of capillaries,

Whereas capillaries have a flattened endothelium, venules are lined by a much taller, cuboidal endothelium. Majno also proposed a mechanism of protein leakage, namely that histamine and other vascular permeabilizing agents induced endothelial cells to contract and pull apart to form intercellular (paracellular) gaps of sufficient size to permit plasma-protein extravasation.

More recently, a structure was discovered in venular endothelium, the vesiculo-vacuolar organelle (VVO), that offers an alternative, trans-endothelial cell route for plasma extravasation in response to permeability factors, VVOs are grape-like clusters comprised of hundreds of uncoated, cytoplasmic vesicles and vacuoles that together form an organelle that traverses venular endothelial cytoplasm from lumen to albumen (Figs.3 (a, b), ​ 4 a).

VVOs often extend to inter-endothelial cell interfaces and their individual vesicles (unlike caveolae) commonly open to the inter-endothelial cell cleft. The vesicles and vacuoles comprising VVOs vary in size from those the size of caveolae to vacuoles with volumes as much as 10-fold larger, These vesicles and vacuoles are linked to each other and to the luminal and abluminal plasma membranes by stomata that are normally closed by thin diaphragms that appear similar to those found in caveolae.

We conjectured some years ago that VVOs formed from the linking together of individual caveolae and that larger vesicles and vacuoles resulted from the fusion of two or more caveolae-sized vesicles, Evidence for this was that the smallest VVO vesicles were indistinguishable structurally from caveolae and larger vesicles and vacuoles have volumes that do not fall on a continuum but have a modal distribution, i.e., occur as multiples of the volume of caveolae, the unit vesicle, up to 10-mers.

However, VVO vesicles and vacuoles only stain irregularly for caveolin (unpublished data), a protein that is demonstrable by electron microscopic immunocytochemistry in nearly all plasma membrane-connected caveolae. Also, whereas the capillaries in caveolin-1 null mice lack caveolae altogether, VVOs are present in normal numbers in the venular endothelium of these mice (unpublished data).

Whether VVOs somehow take the place of caveolae in caveolin-1 null mice and thereby contribute to the increased permeability observed in these animals needs to be investigated. Transmission electron micrographs of venules in normal mouse ear skin ( a, b ) and of a mother vessel ( c, d ) 3 days after local injection of Ad-VEGF-A 164, ( a, b) Typical normal venules lined by cuboidal endothelium. The cytoplasm contains prominent vesiculo-vacuolar organelles (VVOs) and is enveloped by a complete coating of pericytes (P).

1. R, red blood cell.
2. C, d ) MV are greatly enlarged vessels that are characterized by extensive endothelial cell thinning; striking reduction in VVOs and other cytoplasmic vesicles; prominent nuclei that project into the vascular lumen; frequent mitotic figures (arrows, c ); endothelial cell bridging with the formation of multiple lumens (L, d ); and pericyte (P) detachment in ( c ).

The mother vessel lumen ( c ) is packed with red blood cells, indicative of extensive plasma extravasation. Inset. The normal venule depicted in a is reproduced in c at the same magnification as the mother vessel to illustrate differences in relative size of normal venules and MV. ( a ) Schematic diagram of a normal venule comprised of cuboidal endothelium with prominent VVOs and closed inter-endothelial cell junctions. Note that some VVO vesicles attach to the intercellular cleft below the tight and adherens junction zones.1 and 2 indicate potential pathways for transcellular (VVO) and intercellular (paracellular) plasma extravasation, respectively.

1. Basal lamina (BL) is intact and the endothelium is completely covered by pericytes.
2. B ) AVH.
3. Acute exposure to VEGF-A causes VVO to open, allowing transcellular passage of plasma contents, possibly by mechanical pulling apart of stomatal diaphragms (3).
4. Others have suggested that fluid extravasation takes place through an opening of intercellular junctions (4, here shown closed).

BL and pericyte coverage are as in ( a ). ( c ) CVH. Prolonged VEGF-A stimulation causes venular endothelium to transform into MV, greatly thinned, hyperpermeable cells with fewer VVOs and VVO vesicles/vacuoles, degraded BL, and extensive loss of pericyte coverage.

Plasma may extravasate either through residual VVO vesicles (5) or through fenestrae (6) Although very little is known about the mechanisms of VVO function, it is clear that, upon exposure to histamine, VEGF-A, etc., macromolecular tracers such as ferritin pass through a sequence of inter-connected VVO vesicles and vacuoles from the vascular lumen to the albumen (Fig.4 b) It seems that vascular permeability inducing agents cause the diaphragms interconnecting vesicles and vacuoles to open, thereby providing a transcellular pathway for plasma and plasma-protein extravasation.

The underlying mechanism could be mechanical, as was the endothelial cell contraction mechanism originally postulated by Majno, If so, the actin–myosin contractions induced by permeability factors would act to pull apart the diaphragms linking adjacent VVO vesicles and vacuoles, resulting in a transcellular rather than an inter-endothelial cell (paracellular) route for plasma extravasation.

Why does vasodilation occur in inflammation?

Inflammation – Inflammation can occur due to a variety of injuries, diseases, or conditions. Vasodilation happens during the inflammatory process in order to allow increased blood flow to the affected area. This is what causes the heat and redness associated with inflammation.

What are the four systemic signs of acute inflammation?

Clinical Significance – The signs of inflammation include loss of function, heat, pain, redness, and swelling. Inflammation is part of the body’s complex biological response to harmful stimuli, such as irritants, pathogens, and damaged cells. It is clinically useful to differentiate inflammation and infection as there are many pathological situations where distinguishing them is highly essential to evaluation and treatment.

What are the 2 major vascular pathways?

Overview of the Vascular System The vascular system, also called the circulatory system, is made up of the vessels that carry blood and lymph through the body. The arteries and veins carry blood throughout the body, delivering oxygen and nutrients to the body tissues and taking away tissue waste matter.

Arteries. Blood vessels that carry oxygenated blood away from the heart to the body. Veins. Blood vessels that carry blood from the body back into the heart. Capillaries. Tiny blood vessels between arteries and veins that distribute oxygen-rich blood to the body.

Blood moves through the circulatory system as a result of being pumped out by the heart. Blood leaving the heart through the arteries is saturated with oxygen. The arteries break down into smaller and smaller branches to bring oxygen and other nutrients to the cells of the body’s tissues and organs.

1. As blood moves through the capillaries, the oxygen and other nutrients move out into the cells, and waste matter from the cells moves into the capillaries.
2. As the blood leaves the capillaries, it moves through the veins, which become larger and larger to carry the blood back to the heart.
3. In addition to circulating blood and lymph throughout the body, the vascular system functions as an important component of other body systems.

Examples include:

Respiratory system. As blood flows through the capillaries in the lungs, carbon dioxide is given up and oxygen is picked up. The carbon dioxide is expelled from the body through the lungs, and the oxygen is taken to the body tissues by the blood. Digestive system. As food is digested, blood flows through the intestinal capillaries and picks up nutrients, such as glucose (sugar), vitamins, and minerals. These nutrients are delivered to the body tissues by the blood. Kidneys and urinary system. Waste materials from the body tissues are filtered out from the blood as it flows through the kidneys. The waste material then leaves the body in the form of urine. Temperature control. Regulation of the body’s temperature is assisted by the flow of blood among the different parts of the body. Heat is produced by the body’s tissues as they go through the processes of breaking down nutrients for energy, making new tissue, and giving up waste matter.

What are the 5 P’s of vascular disease?

The 5 P’s of circulation assessment includes pain, pallor, pulse, paresthesia, and paralysis.

What are the 6 P’s of vascular disease?

History and Physical – The classic presentation of acute arterial occlusion involves the “six Ps” pallor, pain, paresthesia, paralysis, pulselessness, and poikilothermia. These clinical manifestations can occur anywhere distal to the occlusion. Most patients initially present with pain, pallor, pulselessness, and poikilothermia.

Pain is often localized and less severe when the limb is in the dependent position. As the ischemia prolongs, paresthesia replaces pain, and the final stages of injury cause paralysis. Patients with embolic occlusion tend to have an abrupt onset with more severe symptoms, as collateralization of the vasculature has not occurred at this point.

It is essential to realize that symptoms can develop over the course of hours to days and present as new or recurring. Low kidney function has been linked with the development of arterial occlusive disease. A study conducted in Japan found advanced chronic kidney disease to be an independent risk factor.

What are the stages of vascular injury?

Pulling or tearing a muscle is a common injury we see in clinic – but what actually happens in the healing process and what can you do to help? There are three main phases to healing: the inflammatory, the proliferation and the remodelling. But before we get onto these let’s take a look at the three grades of muscle tear.

What are vascular changes?

Vascular disease (vasculopathy) affects the blood vessels that carry oxygen and nutrients throughout your body and remove waste from your tissues. Common vascular problems happen because plaque (made of fat and cholesterol) slows down or blocks blood flow inside your arteries or veins.

What causes vascular permeability in acute inflammation?

Acute vascular hyperpermeability (AVH) – A rapid increase in vascular permeability occurs when the microvasculature is exposed acutely to any of a number of vascular permeabilizing factors, e.g., VEGF-A, histamine, serotonin, PAF, etc. Some of these agents (e.g., histamine, serotonin, VEGF-A) are normally stored in tissue mast cells and so may be released by agents that cause mast cell degranulation, e.g., allergy, insect bites, etc.

1. Single exposure to any of these permeability factors results in a rapid but self-limited (complete by 20–30 min) influx of plasma into the tissues.
2. Not only is the quantity of extravasated fluid greatly increased above that found in BVP but its composition is greatly changed.
3. As already noted, the fluid passing from the circulation into normal tissues under basal conditions is a plasma filtrate, i.e., a fluid consisting largely of water and small solutes but containing very little plasma protein.

However, the fluid that extravasates in AVH is rich in plasma proteins, approaching the levels found in plasma, and is referred to as an exudate, Among the plasma proteins that extravasate are fibrinogen and various members of the blood clotting cascade.

When these come into contact with tissue factor, a protein that is normally expressed by many interstitial cells, the clotting system is activated and the exudate clots to deposit fibrin, Fibrin forms a gel that traps water and other solutes, restraining their clearance by lymphatics or capillaries and resulting in tissue swelling (edema).

Fibrin in tissues has other functions that are discussed below. However, as long as the permeability stimulus is not continuous, the deposited fibrin is rapidly degraded without further consequences. AVH also differs from BVP in that, as Guido Majno demonstrated, the vascular leakage takes place not from capillaries but from post-capillary venules, highly specific vessels just downstream of capillaries,

1. Whereas capillaries have a flattened endothelium, venules are lined by a much taller, cuboidal endothelium.
2. Majno also proposed a mechanism of protein leakage, namely that histamine and other vascular permeabilizing agents induced endothelial cells to contract and pull apart to form intercellular (paracellular) gaps of sufficient size to permit plasma-protein extravasation.

More recently, a structure was discovered in venular endothelium, the vesiculo-vacuolar organelle (VVO), that offers an alternative, trans-endothelial cell route for plasma extravasation in response to permeability factors, VVOs are grape-like clusters comprised of hundreds of uncoated, cytoplasmic vesicles and vacuoles that together form an organelle that traverses venular endothelial cytoplasm from lumen to albumen (Figs.3 (a, b), ​ 4 a).

1. VVOs often extend to inter-endothelial cell interfaces and their individual vesicles (unlike caveolae) commonly open to the inter-endothelial cell cleft.
2. The vesicles and vacuoles comprising VVOs vary in size from those the size of caveolae to vacuoles with volumes as much as 10-fold larger,
3. These vesicles and vacuoles are linked to each other and to the luminal and abluminal plasma membranes by stomata that are normally closed by thin diaphragms that appear similar to those found in caveolae.

We conjectured some years ago that VVOs formed from the linking together of individual caveolae and that larger vesicles and vacuoles resulted from the fusion of two or more caveolae-sized vesicles, Evidence for this was that the smallest VVO vesicles were indistinguishable structurally from caveolae and larger vesicles and vacuoles have volumes that do not fall on a continuum but have a modal distribution, i.e., occur as multiples of the volume of caveolae, the unit vesicle, up to 10-mers.

• However, VVO vesicles and vacuoles only stain irregularly for caveolin (unpublished data), a protein that is demonstrable by electron microscopic immunocytochemistry in nearly all plasma membrane-connected caveolae.
• Also, whereas the capillaries in caveolin-1 null mice lack caveolae altogether, VVOs are present in normal numbers in the venular endothelium of these mice (unpublished data).

Whether VVOs somehow take the place of caveolae in caveolin-1 null mice and thereby contribute to the increased permeability observed in these animals needs to be investigated. Transmission electron micrographs of venules in normal mouse ear skin ( a, b ) and of a mother vessel ( c, d ) 3 days after local injection of Ad-VEGF-A 164, ( a, b) Typical normal venules lined by cuboidal endothelium. The cytoplasm contains prominent vesiculo-vacuolar organelles (VVOs) and is enveloped by a complete coating of pericytes (P).

1. R, red blood cell.
2. C, d ) MV are greatly enlarged vessels that are characterized by extensive endothelial cell thinning; striking reduction in VVOs and other cytoplasmic vesicles; prominent nuclei that project into the vascular lumen; frequent mitotic figures (arrows, c ); endothelial cell bridging with the formation of multiple lumens (L, d ); and pericyte (P) detachment in ( c ).

The mother vessel lumen ( c ) is packed with red blood cells, indicative of extensive plasma extravasation. Inset. The normal venule depicted in a is reproduced in c at the same magnification as the mother vessel to illustrate differences in relative size of normal venules and MV. ( a ) Schematic diagram of a normal venule comprised of cuboidal endothelium with prominent VVOs and closed inter-endothelial cell junctions. Note that some VVO vesicles attach to the intercellular cleft below the tight and adherens junction zones.1 and 2 indicate potential pathways for transcellular (VVO) and intercellular (paracellular) plasma extravasation, respectively.

Basal lamina (BL) is intact and the endothelium is completely covered by pericytes. ( b ) AVH. Acute exposure to VEGF-A causes VVO to open, allowing transcellular passage of plasma contents, possibly by mechanical pulling apart of stomatal diaphragms (3). Others have suggested that fluid extravasation takes place through an opening of intercellular junctions (4, here shown closed).

BL and pericyte coverage are as in ( a ). ( c ) CVH. Prolonged VEGF-A stimulation causes venular endothelium to transform into MV, greatly thinned, hyperpermeable cells with fewer VVOs and VVO vesicles/vacuoles, degraded BL, and extensive loss of pericyte coverage.

Plasma may extravasate either through residual VVO vesicles (5) or through fenestrae (6) Although very little is known about the mechanisms of VVO function, it is clear that, upon exposure to histamine, VEGF-A, etc., macromolecular tracers such as ferritin pass through a sequence of inter-connected VVO vesicles and vacuoles from the vascular lumen to the albumen (Fig.4 b) It seems that vascular permeability inducing agents cause the diaphragms interconnecting vesicles and vacuoles to open, thereby providing a transcellular pathway for plasma and plasma-protein extravasation.

The underlying mechanism could be mechanical, as was the endothelial cell contraction mechanism originally postulated by Majno, If so, the actin–myosin contractions induced by permeability factors would act to pull apart the diaphragms linking adjacent VVO vesicles and vacuoles, resulting in a transcellular rather than an inter-endothelial cell (paracellular) route for plasma extravasation.