Vascular Remodelling Flashcards
What is the interstitial ECM?
This refers to the matrix surrounding the intima, media and adventitia, each having their own unique composition with varying function.
What comprises the endothelial basement membrane?
The basement membrane comprises type IV collagen, lamin, and HSPGs.
What is the composition of the ECM in the intima?
The ECM in the intima (before the internal elastic lamina) is proteoglycan rich.
What is the composition of the ECM in the media?
The ECM in the media (between the internal and external elastic lamina) is composed of type I and III collagen, fibronectin and dermatan/chondroitin sulphate proteoglycans.
What is the composition of the ECM in the adventitia?
The ECM in the adventitia (after the external elastic lamina) contains fibroblasts, fat cells and otherwise unremarkable matrix components.
What is the role of the interstitial matrix?
The ECM of the arterial wall interacts with many components of the blood and modulates intercellular interactions. Its roles include:
• Framework/Structural Integrity
• Provision of a permeable barrier for plasma components
• Sequestration/retention of various molecules
• Modulates intercellular signalling
What molecules are sequestered/retained by the interstitial matrix?
o Signalling molecules (cytokines, hormones)
o Enzymes
o Lipids
ApoB100 has strong binding to the proteoglycans through their +ve and -ve charges respectively
How does the interstitial matrix modulate intercellular signalling?
o Integrins regulate cell signalling processes that modulate contraction and vascular remodelling
o SMC Phenotype is affected by the ECM composition
More fibronectin increases proliferation
More laminin and collagen (IV) is anti-proliferative
o Thrombotic regulation – expression of anticoagulant glycosaminoglycans such as heparin
What is myogenic tone?
Myogenic tone is the contraction of the blood vessel stimulated by the increased shear force that results from hypertension. This allows it to retain its lumen size instead of being stretched by the increased pressure.
How is myogenic tone stimulated?
This is stimulated by the intracellular conversion of free, globular G-actin to filamentous chains of F-actin. This is stimulated by signalling via integrins, which when activated form a complex by phosphorylating and recruiting paxillin and recruiting focal adhesion kinase (FAK), α-actinin and non-Tyr-kinase receptors.
This was discovered by the disruption of myogenic tone that arose from actin polymerisation inhibition.
What signalling factors are produced by the endothelium?
Many of the factors required to maintain quiescence of the SMCs are produced by the endothelium, including those that begin the endothelin pathway, the NO pathway and the prostacyclin pathway.
NO and prostacyclin are both potent anti-proliferative (and vasodilatory) agents, acting via cGMP and cAMP second messengers respectively. Endothelin, meanwhile, serves the opposite function, promoting proliferation and vasoconstriction.
What is prostacyclin? How is it made and received? What are its main effects?
Prostacyclin (AKA Prostaglandin I2) is an eicosanoid lipid produced from arachidonic acid in endothelial cells by prostacyclin synthase.
It acts through the IP receptor to stimulate cAMP, but also directly acts on the nuclear receptor PPARβ.
Reducing thrombosis and SMC proliferation (thus inhibiting remodelling).
How does prostacyclin affect thrombosis?
Prostacyclin is also a potent antithrombotic agent, preventing platelet adhesion to exposed blood vessel wall.
It does this by two mechanisms; inhibiting the interaction between platelet GPIb interaction with vWF and reducing the interaction between platelet GPIIb/IIIa expression and hence interaction with fibrinogen.
How does prostacyclin affect the endothelium?
Although it reduces proliferation of SMCs, prostacyclin is also pro-proliferative for endothelial cells as part of its role in promoting angiogenesis and endothelial repair (re-endothelialisation).
It also makes the endothelial cells more stress resistant and upregulates many responses in endothelial progenitor cells (EPCs) including adhesion, migration and release of angiogenic cytokines.
What is the cumulative effect of the action of prostacyclin?
The cumulative effect of prostacyclin reducing thrombosis and SMC proliferation (and hence vascular remodelling) while stimulating re-endothelialisation and angiogenesis is that it has anti-atherothrombotic and anti-ischemic effects.
What is vascular remodelling?
Remodelling is the alteration in structure of the vascular wall, often associated with hypertension or atherosclerosis. It is largely characterised by swelling or shrinkage of the media, or migration of SMCs into the intima.
Remodelling is generally done as a response to a change in wall stress, in an attempt to normalise it.
What effect does oxidative stress have on remodelling? What mediates this?
Oxidative Stress Promotes Remodelling by Reducing NO Bioavailability .
This is often mediated by the increased levels of superoxide that result from oxidative stress, a common occurrence in atherosclerosis. Under such conditions, NADPH oxidase and Xanthine oxidase produce the superoxide radicals.
How does oxidative stress reduce NO bioavailability?
Superoxides directly deplete NO by reacting with it to form peroxynitrites.
They also deplete the cofactors for NOS, reducing its production.
Oxidative stress also leads to oxidation/inactivation of guanylyl cyclase, NO’s only receptor.
What effect does superoxide have on NOS?
It depletes the cofactors for NOS, including by oxidation of tetrahydrobiopterin to dihydrobiopterin – decreasing the concentration of the essential cofactor. This leads to ‘NOS uncoupling’ – which leads to the NOS itself produces superoxides.
What effect does oxidative stress have on NO receptors?
Within the smooth muscle itself, the NO usually binds to the haem group of soluble guanylyl cyclase – the only receptor of NO.
However, when the haem group is oxidised NO is unable to bind, and hence unable to stimulate its response. Oxidative stress also leads to haem loss, and subsequent proteasome degradation of the guanylyl cyclase.
How is the reduction in NO bioavailability due to oxidative stress targeted in therapy?
Many therapeutics have targeted this dysfunction, including cyclase activators which can activate the guanylyl cyclase independently and in fact stimulate NO binding.
These have been shown to prevent leukocytes from sticking to the lumen wall, hence reducing infiltration. This is effected by the reduced expression of adhesion molecules such as P-selectin that is stimulated by the NO pathway.
How is vasoconstriction associated with vascular remodelling?
Vasodilatory and vasoconstrictory factors form a dynamic balance to modulate the blood vessel. They also affect thrombosis and the vascular remodelling process.
Vasodilatory factors such as NO, prostacyclin, Vasoactive Intestinal Peptide and assorted potassium channels resisting remodelling while vasoconstriction-promoting factors such as endothelin, thromboxane, angiotensin II, serotonin and growth factors promote remodelling.
What is the quiescent SMC phenotype?
In their quiescent state the SMCs have a contractile, spindle-shaped phenotype, with many myofilament bundles. They are non-proliferating and non-migratory (being more susceptible to growth inhibitors such as NO and ApoE). Quiescent SMCs posess the contractile fibers that cross the cell to expand and contract it.
How do quiescent SMC interact with the ECM?
They are instead fixed into the ECM and to each other through focal adhesions and integrin receptors which restrain them in the insterstitial matrix preventing migration into the intima and allowing for inhibitory integrin-matrix signalling.
