Ricard et al 2021 Endothelium Flashcards
What are broad functions of the endothelium?
BBB, angiogenesis, oxygen and nutrient supply, coagulation, vascular tone, immune cell trafficking and inflammation
Are vascular and lymphatic endothelial cells heterogenous?
Vascular endothelial cells are heteregenous by organs by lymphatic vessels are similar throughout
Are endothelial quiescent in its normal state? Are they inactive?
What do these mean?
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.
What are 3 major types of capillaries? Describe them
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.
Describe the FGF signaling pathway. What is it important for?
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
What happens if you inhibit FGFs?
It can cause permeability
Also increases in inflammatory molecules like TGFbeta
What is the mechanism that loss of FGFs cause permeability?
Loss of FGF signal decreases phosphatase SHP2 -> increased phosphorylation of VE-cadherin -> destabilize
How does FGF signaling affect endothelial growth?
Required for the expression of VEGF receptors -> angiogenesis
How is FGF signaling related to shear stress and atherosclerosis?
Disturbed or high shear stress can reduce FGFR expression and promote pro-inflammatory environment via TGFBeta
What is VEGF signaling for?
Angiogenesis
Describe the VEGF signaling pathway
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
What is the role of VEGF in fenestrated capillaries?
Maintains fenestrations
What does depleting VEGF do in mice?
Causes multiorgan hemorrhage and death
What signaling pathways are modulated by shear stress?
FGF and VEGF signaling
Also BMP-Alk1 signaling
How are VEGFRs involved in vasodilation? What are the proteins involved?
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
What detrimental consequences can arise from blocking VEGF signaling?
Reduced eNOS and NO, increased ET-1 -> hypertension
What detrimental consequences can arise from blocking VEGF signaling?
Reduced eNOS and NO, increased ET-1 -> hypertension
What happens in ERK1/2KO?
Increased TGFBeta and decreased eNOS/increased ET1 -> hypertension
Loss of fenestrations
Basically a combination of FGF and VEGF block phenotype
What is WNT signaling important for?
Maintaining tight junctions
Describe the canonical WNT signaling pathway
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
What genes are upregulated by WNT signaling?
Claudin-5 and Glut1 genes
What happens if Wnt signaling is impaired?
Causes BBB leakage and subsequent hemorrhage and seizures
What is Sonic Hedgehog signaling important for?
Maintaining BBB
How does SHH signaling maintain BBB? Where does SHH come from?
Regulating expression of Claudin, occludin, and ZO1
SHH secreted from astrocytes
What happens with impaired SHH signaling?
Decrease expression of junctional proteins and increased expression of ICAM1 -> proinflammatory
What diseases is Wnt signaling implicated in?
AD and MS
What does Angiopoietin1/2 do via Tie2?
Ang1 under normal condition maintains junction
During inflammation or hypoxia, Ang2 expression increases and competes for Tie2 to antagonize -> weaken cell junction
What kind of diseases is Tie2 involved in?
Overactive Tie2 can cause venous malformation
What is BMP signaling for? What does its impairment cause?
Vessel development
Impairment causes arteriovenous malformation and pulmonary arterial hypertension
What is the TGFBeta pathway important for? What does the activation of TGFBeta receptors cause in adults?
Cerebral and coronary vessel development in embryos
In adults, activation can cause transition to mesenchymal characteristics
inflammation, junctional rearrangement, increased ECM protein (rigidity), hypertension
What pathways inhibit the TGFBeta receptor pathway in adults?
VEGF/FGF ERK signaling and BMP-Alk1 signaling
What disease does TGFbeta activation involved in?
atherosclerosis
Is a chemoattractant and survival signal for monocytes -> plaque buildup
