Ricard et al 2021 Endothelium

Question 1

What are broad functions of the endothelium?

Answer 1

BBB, angiogenesis, oxygen and nutrient supply, coagulation, vascular tone, immune cell trafficking and inflammation

Question 2

Are vascular and lymphatic endothelial cells heterogenous?

Answer 2

Vascular endothelial cells are heteregenous by organs by lymphatic vessels are similar throughout

Question 3

Are endothelial quiescent in its normal state? Are they inactive?
What do these mean?

Answer 3

Endothelial cells are quiescent in nature because they don’t proliferate or migrate, with minimal leakage and leukocyte adhesion.
That is not to say that they are not active, they secrete endocrine molecules and maintain barrier maintenance.

Question 4

What are 3 major types of capillaries? Describe them

Answer 4

Continuous, fenestrated, discontinuous
fenestrated has pores that allow fluids and solutes but not macromolecules, found in kidneys
Most capillaries are continuous with tight connections and continuous basement membrane.

Question 5

Describe the FGF signaling pathway. What is it important for?

Answer 5

FGF binds FGFRs which are receptor tyrosine kinases that intracellularly activate PI3K-Akt pathway and MAPK pathways in addition to ERK1/2
They are important for blood and lymphatic vessel development and maintaining vascular integrity/permeability

Question 6

What happens if you inhibit FGFs?

Answer 6

It can cause permeability
Also increases in inflammatory molecules like TGFbeta

Question 7

What is the mechanism that loss of FGFs cause permeability?

Answer 7

Loss of FGF signal decreases phosphatase SHP2 -> increased phosphorylation of VE-cadherin -> destabilize

Question 8

How does FGF signaling affect endothelial growth?

Answer 8

Required for the expression of VEGF receptors -> angiogenesis

Question 9

How is FGF signaling related to shear stress and atherosclerosis?

Answer 9

Disturbed or high shear stress can reduce FGFR expression and promote pro-inflammatory environment via TGFBeta

Question 10

What is VEGF signaling for?

Answer 10

Angiogenesis

Question 11

Describe the VEGF signaling pathway

Answer 11

Similar to FGF signaling
Activates VEGFR (receptor tyrosine kinases) which then activate the PI3K-Akt and MAPK pathways in addition to ERK1/2
ERK1/2 critical for angiogenesis and vessel development

Question 12

What is the role of VEGF in fenestrated capillaries?

Answer 12

Maintains fenestrations

Question 13

What does depleting VEGF do in mice?

Answer 13

Causes multiorgan hemorrhage and death

Question 14

What signaling pathways are modulated by shear stress?

Answer 14

FGF and VEGF signaling
Also BMP-Alk1 signaling

Question 15

How are VEGFRs involved in vasodilation? What are the proteins involved?

Answer 15

VEGFR2 forms a complex with VE-cadherin and platelet endothelial cell adhesion molecule -> allows to sense shear stress
Increased shear stress can activate VEGFR2 independent of ligand -> Akt -> eNOS -> dilation

Question 16

What detrimental consequences can arise from blocking VEGF signaling?

Answer 16

Reduced eNOS and NO, increased ET-1 -> hypertension

Question 17

What detrimental consequences can arise from blocking VEGF signaling?

Answer 17

Reduced eNOS and NO, increased ET-1 -> hypertension

Question 18

What happens in ERK1/2KO?

Answer 18

Increased TGFBeta and decreased eNOS/increased ET1 -> hypertension
Loss of fenestrations
Basically a combination of FGF and VEGF block phenotype

Question 19

What is WNT signaling important for?

Answer 19

Maintaining tight junctions

Question 20

Describe the canonical WNT signaling pathway

Answer 20

Wnt ligands bind the frizzled receptors and LRP5/6 coreceptors. Phosphorylating LRPs recruits Beta catenin destruction complex to the plasma membrane away from Beta catenin so allows target gene transcription

Question 21

What genes are upregulated by WNT signaling?

Answer 21

Claudin-5 and Glut1 genes

Question 22

What happens if Wnt signaling is impaired?

Answer 22

Causes BBB leakage and subsequent hemorrhage and seizures

Question 23

What is Sonic Hedgehog signaling important for?

Answer 23

Maintaining BBB

Question 24

How does SHH signaling maintain BBB? Where does SHH come from?

Answer 24

Regulating expression of Claudin, occludin, and ZO1
SHH secreted from astrocytes

Question 25

What happens with impaired SHH signaling?

Answer 25

Decrease expression of junctional proteins and increased expression of ICAM1 -> proinflammatory

Question 26

What diseases is Wnt signaling implicated in?

Answer 26

AD and MS

Question 27

What does Angiopoietin1/2 do via Tie2?

Answer 27

Ang1 under normal condition maintains junction
During inflammation or hypoxia, Ang2 expression increases and competes for Tie2 to antagonize -> weaken cell junction

Question 28

What kind of diseases is Tie2 involved in?

Answer 28

Overactive Tie2 can cause venous malformation

Question 29

What is BMP signaling for? What does its impairment cause?

Answer 29

Vessel development
Impairment causes arteriovenous malformation and pulmonary arterial hypertension

Question 30

What is the TGFBeta pathway important for? What does the activation of TGFBeta receptors cause in adults?

Answer 30

Cerebral and coronary vessel development in embryos
In adults, activation can cause transition to mesenchymal characteristics

inflammation, junctional rearrangement, increased ECM protein (rigidity), hypertension

Question 31

What pathways inhibit the TGFBeta receptor pathway in adults?

Answer 31

VEGF/FGF ERK signaling and BMP-Alk1 signaling

Question 32

What disease does TGFbeta activation involved in?

Answer 32

atherosclerosis
Is a chemoattractant and survival signal for monocytes -> plaque buildup