Semester 1 Year 3

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Describe the structure of a blood vessel and identify the cellular components

There are 3 main layers, or tunics, to these vessels. The intima is made of subendothelial space and endothelial cells. This is a single cell layer that functions as the first barrier to blood pathogens and communicates with the vascular smooth muscle. The media is made of vascular smooth muscle and its relaxation/constriction dictates the diameter of the vessel and therefore regulates blood flow and blood pressure. The adventitia or externa is collagen-rich with sympathetic nerves embedded in it. It has an external elastic lamina and sometimes a vaso vasorum where there is blood supply from smaller vessels.
The 3 main layers of the veins and venules are the same as in arteries and arterioles however the externa is thicker in the veins and venules. There are also valves that are present to prevent blood back flow.
Endothelial cells have a specific function that is tissue/organ dependent. They can be involved in; fluid filtration, hormone trafficking, immune cell recruitment and signalling, thrombolysis, lypolysis, vascular tone and more!

Understand the mechanisms by which the body can regulate blood flow and pressure

The vasculature is like plumbing taking blood towards target organs and tissues. Systemic arteries, arterioles, and capillaries take oxygenated blood from the left ventricle to the body. Systemic veins, venules, and capillaries carry deoxygenated blood and waste from the periphery to the right atria. The blood then travels through the heart and into the pulmonary blood vessels where the blood is reoxygenated at the lungs and returned to the heart for circulation.
Blood pressure is the pressure of blood on the vessel wall and tight regulation of this is essential for optimal oxygen and nutrient delivery. If the vessel diameter is wide it tends to have low pressure and if the vessel diameter is small it has a higher pressure. Blood pressure also differs between vessel types. The greatest pressure is in the large arteries and reduces as it travels with the lowest pressure being in the large veins.

Discuss the key signaling pathways involved in vascular function and explain how these go wrong in disease

There are 4 key players in the regulation of vascular tone. The two vasodilators are; nitric oxide and endothelial-derived hyper polarising factor (EDHP). The two vasoconstrictors are; endothelin - 1 and angiotensin II (Ang II).
Once known as endothelium derived relaxing factor, nitric oxide is a vasoactive hormone gas synthesised in the endothelium that diffuses into the sub endothelial space and causes relaxation of vascular smooth muscle.
The production results from stimulation of a GPCR on the endothelial cell. This causes a multi-protein phosphorylation cascade involving PIP2 that ends with IP3 causing intracellular calcium release. This causes calmodulin activation, eNOS activation and finally L-argenine converting to L-citeulline rereleasing NO.
To produce effects it diffuse into the smooth muscle cells and activates guanylyl cyclase which convert GTP to cAMP, which activates PKG which stimulates muscle fibre relaxation.
It is unknown whether EDHF is a substance or an electrical signal but what is known is that it hyper polarises smooth muscle by stimulating K+ efflux causing muscle relaxation. This is very important when NO production is compromised. It also seems to influence organ blood flow more than systemic blood flow.
Endothelin-1 causes vasoconstriction via intracellular Ca2+ release. This activates a GPCR on the smooth muscle. It inhibits eNOS, reduces NO bioavailability and promotes vascular inflammation. There is a negative feedback loop involving increased cAMP and NO.
Produced in the liver as angiotensinogen, converted to angiotensin I by renin from the kidney and finally produced due to ACE. AngII has multiple target tissues and causes constriction via the GCPR signalling and intracellular Ca2+ release. Excessive levels can result in high blood pressure and vascular inflammation.
IN DISEASE
AngII increases its levels and signalling promoting inflammation and smooth muscle proliferation. This creates an atherogenic environment.
Endothelin-1 is a potent inflammatory peptide which promotes oxidative stress and immune cell recruitment in the vessel wall. There is also increased production and processing which suppresses NO signalling and promotes vasoconstriction.
The bioavailability of NO is reduced by the inhibition of eNOS and the production of peroxinitate.
Finally there is decreased production and transport of EDHFs leading to impaired vascular responses.

Explain current pharmacological strategies to improve vascular reactivity and blood flow

TZDs/glitazones like pioglitazone are PPARɣ agonists. They cause increased insulin sensitivity, increased HDL cholesterol and have an anti-inflammatory effect in the vessel wall.
Biguanides like metformin take part in complex 1 inhibition and so; regulate glucose metabolism, increase FA oxidation and reduce inflammation.
Statins like simvastatin are cholesterol biosynthesis inhibitors that increase HDL levels, decrease LDL levels and oxidation.
Antioxidants like vitamin C or E reduce ROS and reduce LDL oxidation.
NO donors like diazeniumdiolates and S-nitrosthiols can improve vasoresponsiveness.
ACE inhibitors like coptopril and benazepril reduce AngII production, alleviate vasoconstriction and reduce blood pressure.
Endothelin receptor antagonists like sitaxsentan and ambrisentan seem to have limited effectiveness.
Endothelin converting enzyme inhibitors are current untested in humans.
Surgery is the final option.