Endothelial cells Flashcards
What does the vascular network regulate?
- molecule and cell movement
- physiological responses by different organs
- pathogenic infection and immune responses
- disease states e.g. cancer, heart disease
What are disease states linked to endothelial dysfunction?
cancer heart attacks strokes PAD preeclampsia Dementia
blood vessels?
Artery Arteriole Capillary Venule Vein
What is the blood pressure in arteries, veins and capillaries?
arteries - 80-120 mm Hg
Vein - 30 mm Hg
Capillary 8-10 mm Hg
What is the structure of the capillary?
thin endothelial barrier between ECM and blood
fenestrations
What is endothelial heterogeneity?
input-output device
responds to both biochemical and mechanical changes
cells slightly different based on where they are
What is endothelial input-output activity?
- cell adhesion
- response to grwoth factors
- interaction with migrating cells
- balance between quiescence, proliferation and death
What are the key physiological features of endothelial cells?
- vasculogenesis
- angiogenesis
- vascular homeostasis
- blood clotting
- disease related functions
What is the endothelial balancing act?
need to balance action as this effects ability to deal with major disease states
How is angiogenesis involved in cancer?
growth depends on it
metastasis via spread of tumour cells
How does hypoxia stimulate angiogenesis?
synthesis of pro-angiogenic factors
VEGF-A synthesis
What is angiogenesis dependent on?
HIF-1 activity
synthesis of VEGF-A - binds to cognate receptors
block interactions to treat cancer e.g. Avastin, Sutent
What is the oxygen-regulated HIF-1 switch?
availability of different sets of genes
What is the variety in VEGF receptors
RTKs
Non-RTKs
Non-RTK
What is involved in VEGFR of growth and survival?
confluent cell monolayer = survival response to VEGF-A
Sub-confluent cells = growth response to VEGF-A
What is endothelial sprout organsiation?
when VEGF hits a blood vessel = sprout
blood vessel sprout express DII4 ligands
Stalk cells express Notch and VEGFR2
What are endothelial signalling pathways?
VEGFR2 signalling - positively regulates angiogenesis
Notch signalling negatively regulates angiogenesis
What are endothelial-leukocyte interactions?
PECAM-1 - binding between endothelial cells and leukocytes
VCAM-1 - binds a4b1 integrin
help leukocyte roll and firmly adhere
What is Trans-Endothelial Migration (TEM)
Diapedesis
leukocyte squeezes between 2 endothelial cells
leukocyte moves into the ECM layer
EC-EC connections have to be disrupted and reformed
What is Atherosclerosis?
- Plaques/lesions
- Fat-filled streaks or lesions
- Major artery blockage by blood clots
- causes heart attacks/strokes
How are endothelium-leukocyte interactions important in atherosclerosis?
- monocytes bind to endothelium - differentiate into macrophages which bind modified LDLs
- die and form lesions in vessel wall
What is atherosclerotic Plaque Rupture?
damaged endothelium Blood clot/thrombus Increased blood pressure arterial blockage clinical symptoms
what is the role of NO?
vascular smooth muscle relaxation
blocks leukocyte adhesion
blocks platelet aggregation
What is Endothelial Stem Cell Therapy?
isolation of EPCs
Differentiation in vitro to ECs
Re-implantation of differentiated cells into damaged tissue in vivo e.g. damaged heart or blood vessel tissues
What is endothelial progenitor cell therapy?
isolation of EPCs
differentiation in vitro
Re-implantation into damaged tissue in vivo e.g. damaged heart
What are endothelial derived tumours?
KSHV
- linked to HIV
- infects endothelial cells
- Forms metastatic tumours
What is KSHV-mediated endothelial transformation?
KSHV encoded gene mediates endothelial cell transformation
viral GPCR blocks cell death
elevates signalling and expression of growth factors
proliferate and behave like typical transformed cancer cell - express lytic genes that induce paracrine angiogenesis
also latent phenotype with transcriptional reprogramming
