There are 3 layers of the vascular system:

1. Endothelium- made of single layer of cells, inner lining

2. Tunica Media- bulk of arterial wall, vascular smooth muscle, 2 different functional shapes

   1. Contractile phenotype- contract in response to various stimuli, are in a basal contractile state to maintain arterial tone, can acutely contract or relax in response to certain stimuli to increase or decrease pressure.

   2. Secretory vascular smooth muscle cells- can either be formed “de novo”(from circulating progenerator cells) or can form by transforming contractile smooth muscle cells governed by local factors; these cells are less capable of contraction, more capable of proliferation and secretion (hormones and proteins), proteins are secreted into matrix, and precipitate into the intracellular space (Collagen and elastin), these proteins change the intracellular environment and change the elastic properties of arterial wall and change arterial diameter, these cells are turned on when pathological processes are taking place, such as a tear due to a sudden increase in blood pressure, repair mechanisms kick in, clotting factors are turned on (platelets and other clotting factors), a blood clot is formed initiating the process to transform contractile cells to secretory cells.

3. Adventia

Contractile cells can be influenced by factors that came from endothelia aspect or via factors that are released from nerve endings that terminate on the adventia (sympathetic and parasympathetic).

Endothelia- blood borne hormones can originate in any distant site or be generated in endothelial cells themselves. Physical force (pressure and flow) can cause local modulators to change hormones and peptides that are being secreted. An example of flow is shear stress which is a major modulator of secretory function.

Major Agents that act via Endothelium

Angiotensin II

Its circulating pretenser is Angiotensin I that gets converted to Angiotensin II by ACE (angiotensin converting enzyme) on the endothelia cells, Angiotensin II acts via AT 1 receptors to causing contraction of the vascular smooth muscle (vasoconstriction), causing an increase in blood pressure. Angiotensin II can also come directly from the circulation and act on vascular smooth muscle.

Endothelin (ET 1)

Is generated only by endothelia cells (it has no importance as a circulating hormone); therefore it acts via paracrine action, it increases the contractility of vascular smooth muscle cells. ET 1 acts via ET_A receptors. Factors such as an increase in blood pressure, glucose, and insulin cause an increase in ET-1 production followed by its release and subsequent increase in contraction of vascular smooth muscle.

Sympathetic control

Release via adventia

Adrenaline (ADR) and Noradreline (NA) can act via the blood as well (i.e. somewhat in circulation) these can cause an increase in contractility acting mainly through alpha-1 receptors but can also act via alpha-2 receptors. Cause vasorelaxation (vasodilatation) via beta-2 receptors (thereby decreasing blood pressure).

ANP (atrial nautric peptide)

One of a family of hormones that is released, (in kidneys it cause an excretion of sodium) in vascular smooth muscle it causes vasodilatation, this hormone is released from the heart in response to an increase in blood volume, working to decrease blood pressure, it offsets a high volumic state by acting on kidneys.

Basic mechanisms for vascular smooth muscle cell receptors

G-protein coupled receptors- actions are slower (seconds to minutes)

Ligand gated channels- actions are faster (milliseconds) are used were immediate action is needed.

Example- Angiotensin II will act via Ligand gated channels causing a rapid influx of calcium. At the same time Angiotensin II will act via g-protein coupled receptors to release IP3 that will release calcium from intercellular stores such as endoplasmic reticulum for a more sustained response.

Angiotensin II via AT₁ has a positive effect on release of noradrenaline from nerve endings act as an enhancer of sympathetic nerve endings. Use of ACE (angiotensin converting enzyme) or Angiotensin receptor blockers will block this effect and decrease the sympathetic nervous system effectiveness.

Integrins

Are a family of proteins that act as joints between extracellular matrix and cytoskeleton. The extracellular matrix can affect signal transduction, and any change can induce a signal cascade leading to cytoskeleton modification. The extracellular matrix is made of proteins that are extruded by smooth muscle cells, i.e. collagen, elastin, and osteopontin (this protein binds calcium and is found strictly in bone). Vascular smooth muscle cells secrete proteins that act via integrins to modify the same cell. Example proliferating smooth muscle cell also secrete osteopontin, which aids in cell proliferation. The phenotype of neighboring contractile cells by interacting with products of secretory cells modify internal process to become more similar to secretory cells: walls become thicker, less responsive, and move towards luminal or endothelial aspect of the artery causing a bulge. Therefore narrowing the lumen of the artery, this is called myoendoal proliferation. Happens in response to endothelial injury, hypertension, and Hyperlipidemia.

Endothelium

Is a functional critical organ for various release factors

Prostacyclin

Is a prostaglandin, or arachidonic acid product that acts as a vasodilator, anti-coagulant (prevents platelet aggregation), and exerts vascular protective effects such as anti-sceletheric agent (prevent platelet adherence to vascular wall).

Nitrous Oxide (NO)

Expressed in several forms, is made nearly everywhere. Synthesized by enzyme NOS, which uses L-arginine as its substrate releasing NO as its product. There are a few forms of NOS:

Constitutive

Neuronal NOS

eNOS-endothelial cell synthase

Inducible

Can be regulated and rapidly induced by agents such as cytokines

Basic Effect

NO is a potent vasodilating agent, works on vascular smooth muscle to increase cGMP production.

The leading theory on arthrosclerosis is due to lack of NO production in endothelium or increased consumption of NO leads to arterial dysfunction through a long chain of events that lead to arthrosclerosis.

Several agents increase NO generation

• Shear stress

• Acetylcholine

• Insulin (very important will discuss next)

• Estrogen

Insulin is known to increase the uptake of glucose by cells (remember those earlier endo lectures), but as you just noted insulin increase NO generation. Now NO is a potent vasodilator, thus increasing the blood flow. Thus insulin also increases the blood flow, also increasing the flow of glucose to the cells for uptake.

Arthrosclerosis pathogenesis

Injury to endothelial cells leading to dysfunction caused by following steps

Loss of NO, thromobomodulin and tissue plasminogen activator increase release of adhesion molecules, which leads to increased adhesion of monocytes to endothelial layers helping to form early process of arthrosclerosis. This leads to increase in platelet adhesion causing vasoconstriction, and inflammatory response to monocytes.

Angiotensin II

Is a vasoconstrictor directly via AT 1 receptors, which increases vascular tone. It precipitates volume expansion, increases aldosterone production causing increased sodium reabsorption, increases fluid retention via increased ADH secretion

On the cellular level it increases cell proliferation, migration, and hypertrophy.

It also increases PAI-1 (plasminogen activator inhibitor), thereby decreasing production of plasminogen, which deprives us of an anticlotting mechanism, keeping in mind plasminogen absorbs clots,

Bradykinin

Is a vasodilator directly and indirectly, it increases sodium reabsorption in kidney, and increases vascular fluid permeability into intra and extra vascular space, also increases prothrmobolitc activity via increasing t-PA.

ACE

Converts Angiotensin I to Angiotensin II, metabolizes bradykinin to inactive peptides. Using an Ace inhibitor prevents the breakdown of bradykinin.

There are two Angiotensin II receptors with different action up to this point we have only discussed AT-1 receptors that are responsible for vasoconstriction, vascular proliferation, aldosterone secretion, and increased sympathetic tone. However there is a second receptor AT-2 that is responsible for vasodilatation, antiproliferation, and apoptosis.