Lecture 8 - blood vesssels Flashcards
what cells are the building blocks of all new vessels
endothelial
what are differneces in structure between arteries and veins
artieres have thick fibrous/elastic layers
veinds thinner fibrous/elastic layers
have valves
what is the first phase of de novo vessel fomration
vasculogenesis
what does vasculogenesis involve
the differentiation and coalescence of endo progenitors called angioblasts
forming a primitive embryonic plexus
there are two centre of vasculogenesis
the other centre the a/v segregation = go on to form the dorsal aorta and the cardinal vein
where are angioblasts derived from
lateral plate mesoderm
when does vasculogensis occur
early in devleopment
when does the specification for artery or wein of angioblast cells occur
v early in embryo
when extra embryonic tissue
how is the primary plexus shaped
blood flow through = shear stress
what is angiogensis and whats its main role
the sprouting of new vessels from pre-existing
creates most of the mature vascular network
describe differences between angiogen and vasculogen
angiogensis important in shaping lymph vessels
is reactivated in disease or tissue regen
describe the process of angiogenesis
a) tip cell selection = lateral inh of other tc/bm degradation/loss of pericytes/junctional remodel
b) anastamosis - migratory tip cell (gf imp) have invasive behaviour/ stalk cellsrepression of tc fate/formaiton of lumen - when tip cell meet = fuse
c) vessel maturation - ecm deposited/pericyte recruitment/junction stability
what is anastamosis
vessels connecting
on contact with extra cellular tip cells lose motile ptype generate EC-EC junction and fuse with recipient vessels
what are pericytes
cells that wrap around endothelial cells and supress their poliferation and release cell survival factors inc VEGF/ANG1
what model organism utilised to study blood vessel dev
zebrafish - transparent embryo
can inject fluorescent and have live visualisation
what signal is the master regulator of vessel development
VEGF
ko - no formation
what vegfr promote angiogensis
VEGFR2
VEGFR3
VEGFR2/3 heterodimer
how are vegf act
are receptor tyrosine kinases
vegf bind
dimerise / phosphy -act
what vegfr block angiogensis
VEGFR1
sVfGFR1
what vegf released singal are master regulators of angiogenesis and what rec do they bind to
VEGFA = binds to VEGFR2 and VEGFR1 and sVfGFR1 VEGFC = bind VEGFR2/2-3/3
how does VEGFR1 block angiogensis and hence called a decoy
has a higher effinity for VEGFA than VEGFR2 but minimal rtk activity = block VEGFA mediated angiogenic signalling
how si the spatial control of tip and stalk cells regulated by VEGF and notch
lateral inhibiton = spatial control
tip cell induced by VEGF- highVEGFR singal/low notch
VEGFR induce expr of delta in tip cells
results in activation of notch singal in the stalk cell = low VEGF signal and inhibit VEGFR
how does differnetial notch expression in the tip and stalk cells give differnet identity
activated notch - induced expr of VEGFR1downreg expr VEGFR2 - less responsive to VEGF
- tip cells take lead
what are some funcitonal differneces between tip cells and stak cells
tip = extend the filopida /motile/lead new sprouts/guide migration stalk = non motile/trail tip cells/lumen morphogenses/maintain junctions/connect to parent vessel
what occurs if block notch in vessels
hypersprouting - all think are tip cell - more motile etc
what results when there is an imbalance in angiogensis
many disease states
eg paracrine - vegf rel from tumour - incr branch results in abnormal vessels
(norm autocrine rel from endo cells - maintains vascular homeostasis)
what drives the migration of tip cells
filopodia
what oathways guide the tip cell migration
Slit/robo
netrin/unc5b
sema[horin /plexin
what pathways guide tip cell migration through repulsion
Netrin and unc5b
sema3 and plexind1
slit-ROBO
describe the importance of plexind1 and the experiments that showed this
required for intersegmental patterning in the zebrafish
knockdown with morpholino = no regulation in the migration
what pathways guide migration of tip cell through attractin
VEGF-Neuropilin
what signalling regulates endothelial cell guidance
Sena3a2-plxnD1
how does plexind1 regulate vegfr
blocks vegfr signalling via sVEGFR1
what signalling important in specification of arteries and veins
notch
what fate does a high level of notch activty result in
arterial
how does hgih notch result in arterial fate
expr Hey2 - expr EphrinB2
ligand
what notch signalling in venous cells
CoupTFIII expression
what is ptype if ko notch
no arteray vs venous hierarchy
what the ptype of ephrinb2 mice
look similar to ko notch
what is is expressed in venous cells
ephb4
the receptor for ephrin b2
what is ephrin b2
a guidance molecule
ligand
what roel does ephrin-eph singalling normally have
repulsive
bidirectional
what is the result of differential expression of ephrinb2 and ephb4 in A and v
v few places where connect
two distinct vessels form
what is the ptype with ectopic notch signalling
arteriovenous malformations - mess up the intitial segregation
describe the signal and changes that occur when quiescent vessel recieves an angiogensis signal
mmps act on pericytes -detach from mbn
endo cells loosen junctions
incr permeability of endo cells by vegf allows plasma pr to lay down ecm scaffold
integrin signalling - endo cells move more towards ecm surface
