Vascular remodelling Flashcards
What is vascular remodelling?
The active process of altering structure and arrangement of blood vessels through
Cell growth
Cell death
Cell migration
Production or degradation of the ECM
Description of lung resistance
Thin walled
Carries blood from the right ventricles to the lungs
Blood pumped from the heart is around 15 mmHg
What is the equation for calculating PAP?
PAP = (CO x PVR) + PVP
What happens to the blood vessels during pulmonary cardiovascular disease?
The blood vessels and heart develop structural changes
Endothelial is damaged
Heart muscle hypertrophies
What is the formula for calculating resistance?
1 / radius^4
What happens to the heart as pulmonary vascular remodelling progresses?
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
What factors drive pulmonary vascular disease?
Altitude
Chronic hypoxia
Lesions in the endothelial cells
Genetic mutations
How does altitude affect the presentation of pulmonary vascular disease?
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
How does chronic hypoxia affect the presentation of pulmonary vascular disease?
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
What is the effect of HIF 1a?
Increases ROS presence through NADPH oxidase
Heightens the activity of protease
Increase in endothelial cell apoptosis
Drives inflammatory response in the blood vessels
How do lesions in the cell wall affect the presentation of pulmonary vascular disease?
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
What other factors can alter the synthesis of NO and prostacyclin?
Hypoxia - decreases the expression of eNOS and PGI2S
Inflammation - decreases the bioavailability of eNOA by causing its breakdown and inflammaotry mediators drive SM proliferation
How can genetic mutations alter the presentation of pulmonary vascular disease?
Can drive increase in PAP
Mutations in different TGFb family of genes
What scandal was associated with the drug Fen-Pen?
Appetite suppressor
Linked to cause PAH (10-fold increase)
What is PAH?
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
What is the pathophysiology of PAH?
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
What is the relationship between ET and IPAH disease severity?
ET = endothelin
Strong vasoconstrictor
Strong positive correlation between the edothelin levels and increase in pulmonary vascular resistance
Process of remodelling in pulmonary vascular disease
- Endothelial injury
- Phenotype of the endothelial changes
- Shifts the balance to hypertension, cell proliferation anf platelet activation
- In endothelial dysfunctinon, there is adherence of platelets and leukocytes to the lumen of the blood vessel wall
- Serum factors leak into the medial layers and trigger the smooth mucles to produce MMPS and elastases
- Cause the break down of the internal elastic lamina and release of TGFb
- GF cause the smooth muscle cells to grow and migrate into the lumen of the blod vessel wall
- Smooth muscle cell begins to produce own endothelin, endothelin increase in their own expression
What happens if vascular remodelling is left unckecked?
Drives smooth muscle cell proliferation and gross remodelling
Cells produce more growth factors
Leads to presentation of PAH
What are the drug targets in PAH?
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
Which processes do the ETA and ETB drive?
Smooth muscle cell proliferation
Vasoconstriction
