Lecture 4: Angiogenesis Flashcards
Angiogenesis
Formation of new blood vessels by extension/remodeling of existing capillaries
Cellular layers of blood vessels
- Endothelium (intima)
- Media (sm. muscle)
- Adventitia (CT)
Types of capillaries
- Continuous
- Fenestrated
- Discontinuous
Action of angiotensin
RAAS regulation of vasodilation
Angiotensin II -> AT1, AT2 receptors -> vasoconstriction/dilation
Characteristics of endothelial cells
- Most quiescent, gene. stable cells
- Turnover ~100 days
- Contact w/ capillary basement inhibs proliferation
Vasculogenesis
De novo vessel development from vascular progenitors
Arteriogenesis
Formation of mature vessels through differentiation into veins/arteries
Vasculogenesis process
Mesoderm -> hemangioblasts (VEGF, bFGF, Notch, Wnt) -> angioblasts (VEGF, bFGF) -> endothelial cells
Phases of vasculogenesis
- Mesoderm cells -> hemangioblasts -> blood island aggregates
- Angioblast proliferation/differentiation to endothelial cells
- Formation of primary capillary plexus
Blood island aggregate structure
Inner hematopoietic SCs
Outer angioblasts
Types of angiogenesis
- Sprouting
- Non-sprouting/intussusceptive
Sprouting angiogenesis
Formation of new vessel as offshoot of pre-existing one
Non-sprouting/intussusceptive angiogenesis
- Splitting process
- Interstitum invades existing vessels; trans vascular tissue pillars expand
- Splits existing vessels into 2 parts
Sprouting process
- Increase in vessel permeability, loosen pericyte contacts (VEGF), enzymatic degradation of basement
- EC proliferation + directed migration
- EC tubulogenesis; endothelial adherence to create lumen
- Pericytes attach; sprouts fuse w/ others to form capillary network
VEGF gradient response
Sprouting requires sustained GF stim.
Cellular sprouting steps
- Tip/stalk cell selection
- Tip cell navigation, stalk cell proliferation
- Branching coordination
- Elongation of stalk, tip cell fusion, lumen formation
- Perfusion, vessel maturation
Filopodia
Tip cells form filopodia in response to VEGF; senses/follows attracting/repulsion cues (VEGF/Robo4, UNC5B)
Stalk cell stabilization signal
Relies on Notch activity to seal connections w/ other cells
Hypoxia signaling
Hypoxia promotes VEGF, pro-angiogenic factors through HIF-α expression
Angiogenesis switch hypothesis of cancer
Angiogen. depends on activator-inhibitor balance; cancer disrupts this balance and avoids angiogen. inhibs. through pro-angiogen. factor substitution
Tumor angiogenesis morphology
Tumors create leaky, disorganized, immature vessels w/ loose cell-cell interactions; interferes w/ drug delivery, increases tumor invasiveness
