L29 - angiogenesis, VEGFR, hypoxia Flashcards
(19 cards)
what is angiogenesis
- Formation of new blood vessels
(capillaries) from the existing
vasculature - Involves migration and proliferation of
endothelial cells - Grow and regress in healthy tissues
→ functional demands
how do blood vessels originate
mesodermal stem cells –> hemangioblast –>
angioblast –> endothetial
hematopoietic stem cells –> hematopoietic cells
what is vasculogenesis
the origin of blood vessel from angioblasts
steps of vasculogenesis in the vertebrate embryo
- Arteries or veins: Angioblasts derived from lateral mesoderm are committed to become
arteries or veins. - VEGF-A stimulation: Artery precursor cells migrate toward a VEGF-A secreted from cells in the midline.
- Plexus: The migrating arterial angioblasts align into cords forming a plexus
- Dorsal Aorta: Arterial angioblasts combine forming the dorsal aorta.
- Assembly: Intersomite vessels are assembled from endothelial cells
how is vasculogensis directed
growth factors and morphogens e.g. VEGF
how many types of endothetial cells are there
3 - these become arteries, veins, capillaires
differ in membrane structure/thickness
two mechanisms of angiogenesis
Sprouting angiogenesis, Intussusceptive angiogenesis
explain sprouting angiogenesis
Endothelial cells will migrate to the relevant area, proliferating to increase density and then combine to form tubes
explain intussusceptive angiogenesis
Vessel wall extends into the lumen causing a single vessel to split
in two (splitting angiogenesis)
steps in sprouting angiogensis
HYPOXIA
1. Tip cells: Endothelial cells exposed to the highest VEGF-A concentration become tip cells.
2. Filopodia extension: The tip cells lead the developing sprout by extending numerous filopodia.
3. Elongation: The developing spout elongates by proliferation of endothelial stalk cells.
4. Conjoining: The tip cells from two developing sprouts fuse and create a
lumen.
5. Oxygenation: New capillary oxygenates the tissues → ↓ VEGF-A
6. Stabilisation: The newly developed capillary is stabilized by pericyte recruitment and deposition of ECM
how do tip cells work
VEGFR2 is highly concentrated in tip cells, these align with the VEGFA gradient produced in response to hypoxia
what is delta-notch signalling pathway
causes the reduction in tip cell VEGFR expression when two stalk cells meet,
VEGFA induces Delta-like-d (DLL4) → binds to notch receptor
Activation of notch receptor on stalk cell → reduce VEGRF2
what stimulate sprouting angiogenesis
when oxygen sensing mechanisms detect hypoxia → new vessels → meets metabolic need
steps in intussusceptive angiogenesis
- All vessel cells are exposed to VEGF
2a. protrusion of opposing capillary walls
3a. Pillars fuse together
2b. intraluminal sprouting
3b. intraluminal pillar formation - splitting of blood vessels
metabolic regulation of angiogenesis
Oxygen regulation:
- over oxygenation →microvascular rarefaction (capillary dropout)
- hypoxia → capillary formation
- proportional relationship
- increased metabolism → capillary formation
hypertension and rarefaction
- Hypertension → ↑ blood flow to tissues beyond normal oxygen need
- Acute phase: vasoconstriction to limit blood flow → reduce oxygen supply
(functional rarefaction) - Chronic phase: ↓ VEGF and other oxygen-sensitive proangiogenic growth
factor → loss of microvessels (structural rarefaction)
mechanical regulation of angiogenesis
Blood flow creates shear stress → sensed by the endothelial
cells→ cause morphological changes
Shear stress → activates VEGFR2
pathway (independent of VEGF) causing intussusceptive angiogenesis
what elements of endothelial cells recognising sheer stress
caveolae (eNOS), ion channels, cell-cell adhesion molecules (VCAM, ICAM),
promoters of angiogenesis
VEGFR, HIF
