Vascular Remodelling

Question 1

What is the interstitial ECM?

Answer 1

This refers to the matrix surrounding the intima, media and adventitia, each having their own unique composition with varying function.

Question 2

What comprises the endothelial basement membrane?

Answer 2

The basement membrane comprises type IV collagen, lamin, and HSPGs.

Question 3

What is the composition of the ECM in the intima?

Answer 3

The ECM in the intima (before the internal elastic lamina) is proteoglycan rich.

Question 4

What is the composition of the ECM in the media?

Answer 4

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.

Question 5

What is the composition of the ECM in the adventitia?

Answer 5

The ECM in the adventitia (after the external elastic lamina) contains fibroblasts, fat cells and otherwise unremarkable matrix components.

Question 6

What is the role of the interstitial matrix?

Answer 6

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

Question 7

What molecules are sequestered/retained by the interstitial matrix?

Answer 7

o Signalling molecules (cytokines, hormones)

o Enzymes

o Lipids
 ApoB100 has strong binding to the proteoglycans through their +ve and -ve charges respectively

Question 8

How does the interstitial matrix modulate intercellular signalling?

Answer 8

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

Question 9

What is myogenic tone?

Answer 9

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.

Question 10

How is myogenic tone stimulated?

Answer 10

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.

Question 11

What signalling factors are produced by the endothelium?

Answer 11

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.

Question 12

What is prostacyclin? How is it made and received? What are its main effects?

Answer 12

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).

Question 13

How does prostacyclin affect thrombosis?

Answer 13

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.

Question 14

How does prostacyclin affect the endothelium?

Answer 14

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.

Question 15

What is the cumulative effect of the action of prostacyclin?

Answer 15

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.

Question 16

What is vascular remodelling?

Answer 16

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.

Question 17

What effect does oxidative stress have on remodelling? What mediates this?

Answer 17

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.

Question 18

How does oxidative stress reduce NO bioavailability?

Answer 18

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.

Question 19

What effect does superoxide have on NOS?

Answer 19

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.

Question 20

What effect does oxidative stress have on NO receptors?

Answer 20

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.

Question 21

How is the reduction in NO bioavailability due to oxidative stress targeted in therapy?

Answer 21

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.

Question 22

How is vasoconstriction associated with vascular remodelling?

Answer 22

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.

Question 23

What is the quiescent SMC phenotype?

Answer 23

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.

Question 24

How do quiescent SMC interact with the ECM?

Answer 24

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.

Question 25

What change in SMC phenotype occurs in remodelling?

Answer 25

Remodelling signalling stimulates a shift in the equilibrium between the two phenotypes towards the synthetic phenotype, named due to its propensity for secretion of further ECM components (producing 50x more collagen than the normal phenotype cells).

These cells are rhomboid and non-contractile, with far fewer filament bundles, as well as being highly proliferatice and migratory.

Question 26

How are synthetic phenotype SMCs regulated to facilitate remodelling?

Answer 26

The increased mitotis and apotosis is mediated through their fibronectin-integrin interactions which constitute proliferative signalling, as well as decreased susceptibility to growth inhibitors from the endothelium, such as NO, increased inflammatory NF-κB signalling (required for hyperplasia) and increased reponse to growth factors such as PDGF (the bFGF receptor expression increases 20-fold).

They also increase expression of scavenger receptors, leading to foam cell formation.

Question 27

What are the different modes of remodelling?

Answer 27

Remodelling can be inward or outward, depending on whether the lumen diameter is decreasing or increasing respectively.

The remodelled vessels are also described as hypo-, eu- or hypertrophic depending on whether the total cross-sectional area is decreasing, constant or increasing respectively.

Which way the blood vessels are remodelled is dependent on which factors stimulated the remodelling.

Question 28

What stimulates hypertrophic remodelling?

Answer 28

Increased pressure due to hypertension, as well as increased blood flow (thus vasodilation) and factors such as angiotensin lead to increased wall stress.

This results in outward hypertrophic remodelling, in order to reduce the wall stress by thickening the medial layer.

Question 29

What stimulates eutrophic remodelling?

Answer 29

Vasoconstriction leads to an increase in pressure and decrease in diameter.

According to the Laplace relation that characterises these things, this increase in wall thickness and decrease in lumen size results in constancy of wall stress and hence the remodelling is inward, and eutrophic.

Question 30

How is remodelling affected by altitude?

Answer 30

One natural cause of remodelling is at birth, where the vasculature adapts to ex-utero life. Before birth, the pulmonary circulation is at very high pressure (measured by pulmonary artery pressure).

In those born at sea level this rapidly declines into a normal pressure through outward eutrophic remodelling, but those born at high altitude the pressure does decrease but remains generally elevated leading to hypertrophic remodelling with no change in lumen size. This can last for many years in those affected.

Question 31

How does remodelling occur naturally?

Answer 31

Remodelling occurs as a natural part of arteriogenesis (outward remodelling) and vessel regression (inward remodelling).

Question 32

How does remodelling occur in pathological states?

Answer 32

In aneurysm formation the vasculature undergoes outward remodelling due to segmental degradation of the media leading to progressive dilation.

Transplant Vasculopathy is characterised by neo-intima formation and hence inward remodelling due to excessive intimal thickening through SMC recruitment and proliferation.

Question 33

How does hypertension affect remodelling?

Answer 33

Excessive hypertension results in inward eutrophic remodelling, with a decrease in lumen diameter and relative increase in medial cross-sectional area to maintain a constant total diameter.

The media:lumen ratio is indicative of survivability, with a higher ratio (hence more inwardly remodelled) correlating with increased mortality independent of other risk factors.

Question 34

How is hypertension-induced remodelling treated?

Answer 34

This remodelling is reversed by some treatments for hypertension but not others. ACE inhibitors and Ca2+ channel blockers do reverse the remodelling but beta-blockers do not.

Question 35

How does vasoconstriction induce inward eutrophic modelling?

Answer 35

When under high pressure, arterioles are prone to developing spontaneous myogenic tone, a reduction in lumenal size due to SMC contraction which produces lasting cell overlap.

Further constriction induced by vasoconstrictory signalling, through the ECM-Integrin-cytoskeletal axis, leads to acute contraction and further cell overlap, leading to autoregulation of SMC length.

This signalling, as previously described, is a TKR dependent process that is stimulated by tissue-type transglutaminase. The hypertension can also lead to overexpression of the integrins.

The decreased length of the SMCs changes their position within the arterial wall, allowing them to regain the ability to normally constrict and relax with the new smaller circumference.

Question 36

How does atherosclerosis affect remodelling?

Answer 36

As an atheroma grows, the vasculature around it undergoes the common smooth muscle hypertrophy and early intimal thickening.

As this progresses to an irreversible stat, in which the internal elastic lamina is degraded by elastases, there is increased response to brain natriuretic peptide, which fights the inward remodelling by stimulating SMC relaxation.

The latest stage is characterised by the formation of plexiform lesions, complex glomeruloid-like structures produced by disordered angiogenesis which can occlude the lumen.

Question 37

What effect does chronic pulmonary hypertension have on the vasculature?

Answer 37

Chronic pulmonary hypertension leads to vascular pruning, a process in which the smaller blood vessels are lost through necrosis or occlusion, greatly reducing gaseous exchange potential.

Such progression is far faster in children than adults, and is associated with a pattern of expression of various signalling components, including downregulation of the potassium channel Kv1.5.

Question 38

How can atherosclerosis-induced remodelling be treated?

Answer 38

Remodelled pulmonary arteries of this kind have been shown to be ameliorated somewhat by the presence of a stable prostacyclin analogue called treprostinil that is not degraded and so prolongs the signalling response. This is implicated in SMAD1/5 phosphorylation and increased id1 expression.

VEGF signalling is protective in the early stages of the disease, but in the late stages it inhibition protects against endothelial proliferation. VEGF pathway inhibitors such as sorafenib and those that block TKR such as PDGFR and c-Kit.