Vascular remodelling

Question 1

What is vascular remodelling?

Answer 1

The active process of altering structure and arrangement of blood vessels through

Cell growth
Cell death
Cell migration
Production or degradation of the ECM

Question 2

Description of lung resistance

Answer 2

Thin walled

Carries blood from the right ventricles to the lungs

Blood pumped from the heart is around 15 mmHg

Question 3

What is the equation for calculating PAP?

Answer 3

PAP = (CO x PVR) + PVP

Question 4

What happens to the blood vessels during pulmonary cardiovascular disease?

Answer 4

The blood vessels and heart develop structural changes

Endothelial is damaged

Heart muscle hypertrophies

Question 5

What is the formula for calculating resistance?

Answer 5

1 / radius^4

Question 6

What happens to the heart as pulmonary vascular remodelling progresses?

Answer 6

Pulmonary vascular remodelling progresses

Gross strucutural changes to the vessel wall
Fibroblasts
Endothelial
Smooth muscle

Increase in the P of blood going to the heart due to narrowing lumen

Leads to diastolic dysfuction and chamber dilation

Question 7

What factors drive pulmonary vascular disease?

Answer 7

Altitude

Chronic hypoxia

Lesions in the endothelial cells

Genetic mutations

Question 8

How does altitude affect the presentation of pulmonary vascular disease?

Answer 8

When child is born - very high PA

Child living at sea level - mean PA decreases rapidly, becomes normal within a few hours. Vessels thin out in line with P drop

Child living at high altitude - oxygen saturation is lower than normal, associated with a steap rise in PA P

Question 9

How does chronic hypoxia affect the presentation of pulmonary vascular disease?

Answer 9

Hypoxia causes vasoconstriction in the lung

Increases shear stress and increased production of vascular smooth muscle

Increases activity of transcription factors - HIF-a (hypoxia inducible factor 1 a)

Increases muscularization of arteries due to monocyte adhesion

Question 10

What is the effect of HIF 1a?

Answer 10

Increases ROS presence through NADPH oxidase

Heightens the activity of protease

Increase in endothelial cell apoptosis

Drives inflammatory response in the blood vessels

Question 11

How do lesions in the cell wall affect the presentation of pulmonary vascular disease?

Answer 11

Damage to the endothelial layer exposes the underlying muscle layer

Damage decreases the expression of endothelial nitric oxide synthase and prostacyclin synthase

Promotes vasoconstriction and proliferation of the smooth muscle

Question 12

What other factors can alter the synthesis of NO and prostacyclin?

Answer 12

Hypoxia - decreases the expression of eNOS and PGI2S

Inflammation - decreases the bioavailability of eNOA by causing its breakdown and inflammaotry mediators drive SM proliferation

Question 13

How can genetic mutations alter the presentation of pulmonary vascular disease?

Answer 13

Can drive increase in PAP

Mutations in different TGFb family of genes

Question 14

What scandal was associated with the drug Fen-Pen?

Answer 14

Appetite suppressor

Linked to cause PAH (10-fold increase)

Question 15

What is PAH?

Answer 15

Pulmonary arterial hypertension

Rare disease

Half of patients = idiopathic presentation

Common causes:

Schistosomiasis - parasitic infection, increasing and going to be the most prevalent cause of PAH

Connective tissue disease

Question 16

What is the pathophysiology of PAH?

Answer 16

Synthesis of prostacyclin is falling

Synthesis of thromboxane is increased

Caused by the decrease in production of vasodilators and an increase in the production of vasoconstrictors

Question 17

What is the relationship between ET and IPAH disease severity?

Answer 17

ET = endothelin

Strong vasoconstrictor

Strong positive correlation between the edothelin levels and increase in pulmonary vascular resistance

Question 18

Process of remodelling in pulmonary vascular disease

Answer 18

1. Endothelial injury
2. Phenotype of the endothelial changes
3. Shifts the balance to hypertension, cell proliferation anf platelet activation
4. In endothelial dysfunctinon, there is adherence of platelets and leukocytes to the lumen of the blood vessel wall
5. Serum factors leak into the medial layers and trigger the smooth mucles to produce MMPS and elastases
6. Cause the break down of the internal elastic lamina and release of TGFb
7. GF cause the smooth muscle cells to grow and migrate into the lumen of the blod vessel wall
8. Smooth muscle cell begins to produce own endothelin, endothelin increase in their own expression

Question 19

What happens if vascular remodelling is left unckecked?

Answer 19

Drives smooth muscle cell proliferation and gross remodelling

Cells produce more growth factors

Leads to presentation of PAH

Question 20

What are the drug targets in PAH?

Answer 20

Endothelin pathway - antagonists block the ETA and ETB receptors

Nitric oxide - agents that increase bioavailability of cGMP by blocking phosphodiesterase

Prostacyclin - analogues that binds to receptors and promote vasodilation and antiproliferation

Question 21

Which processes do the ETA and ETB drive?

Answer 21

Smooth muscle cell proliferation

Vasoconstriction