The document discusses angiogenesis and vascular development. It provides diagrams of hemangioblast differentiation into angioblasts and endothelial cells that form the primitive vascular networks of the yolk sac, umbilical vessels, and chorionic vasculature. It also summarizes factors involved in vascular development including soluble factors, cell surface receptors, signaling pathways, and transcription factors that regulate processes like cell survival, proliferation, differentiation, and maturation.
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Derived from Poiseuille’:
Where R is resistance, r is radius, is blood viscosity and l is vessel length
'
4
8 l
r
R
η
π
=
η
( )
( )
L
p
r
q η
π 8
/
4
Δ
=
Where r, L are the radius and length of the tube
is the pressure drop along the tube
is the fluid’s viscosity
p
Δ
η
Flowing
Fluids
Blood
Flow
Viscous
Resistance
Examples
with Bernouli
Equation
Poiseuille’s
Law
Describes
Combines with
other factors in
Involve
Under
Describes
Laminar
Flow
Calculation of
Volume Flowrate
Vasolidation
Arterial
Occlusion
Comparison of
Resistance to
flow
Resistance
in series
Vessels
Under
conditions
with smooth
And the
effect of
And
And
allows
But fails to adequately
Illustrated
by
And
Radius
Dependence
Non-
Newtonian
Fluids
describe
And
Length
Dependence
Demonstrating
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Q = volumetric flow rate, in3/sec
μ = viscosity, lb∙sec/in2
8 L
Q
P
μ
=
Δ μ viscosity, lb sec/in
L = tube length, in
R = tube radius, in
1
4
R
P
π
=
Δ
8 L
1
0.5
R = 1 / 14 = 1
R = 0.5 / 0.54 = 16
4
8
tan
Re
R
L
ce
sis
π
η
=
The original form of Bernoulli's equation is:
t
cons
p
gh tan
2
2
=
+
+
ρ
is the fluid velocity at a point on a streamline
g the acceleration due to gravity
h is the height of the point above a reference plane
p is pressure at the point
i h d i f h fl id ll i i h fl id
p
g
2
υ
is the density of the fluid at all points in the fluid
static pressure + dynamic pressure = total pressure
ρ
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Poiseuille’s + Bernoulli’s
Diameter : 4 – 6 X
Exp.Physiol 1997; 82;377 - 87
• Elastic pouch
• Low resistance
• High flow
• Free neurovascular regulation
J Clin Invest 1997;99:2152-2164
Hypertens Pregnancy 1996;15:7-23
Schematic diagram illustrating the contribution of TIMP‐2
and ‐3 to pericyte‐induced vascular tube stabilization
Saunders, W. B. et al. J. Cell Biol. 2006;175:179‐191
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Caniggia
H > 8 PO2 l t 17 9 ( d 6 9) H lif i
Jauniaux : ↑ m RNA & aktifitas katalase, glutation peroksidase,
superoksidismutase plasenta
H 8 – 9 mg : heat shock protein 70 ↑
• H > 8mg : PO2 plasenta 17,9 (sd 6,9) mmHg → proliferasi
• H 12 – 13 mg : PO2 plasenta 60,7 (sd 8,5)mmHg → diferensiasi & invasi
H 8 9 mg : heat shock protein 70 ↑
Nitrotirosin ↑
Aktivitas Mitokondria ↑
Burst oksidatif &
pertumbuhan invasif
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20
25
30
SETDB1
KIAA007
5
10
15
MANBA
RPL13
WBSCR1
0
1 2 3 4
ARPC1B
Kinetics of hypoxia regulation in early (11 weeks) placentas. Six examples of genes exhibiting
a transcriptional arrest under short hypoxic conditions, but coming back to almost normal
levels of expression under extended hypoxic conditions.
BMC Genomics 2005 6:111
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The many facets of PECAM‐1 signaling: a schematic representation of PECAM‐1’s roles as a dynamic modulator of endothelial, hematopoietic precursor cell and
immune cell junctional, cytoskeletal, adhesive, and signaling pathways based on data accrued in the laboratory (1) illustrates the binding of SHP‐1 & ‐2 to differentially
phosphorylated/alternatively spliced PECAM‐1, resulting in distinct binding to PECAM‐1 and substrate specificities. PECAM‐1/SHP‐1 & 2 interactions have been shown
to modulate moesin phosphorylation, affecting directed migration of neutrophils and megakaryocytes; the tyrosine phosphorylation state of beta catenin and FAK (not
shown), affecting vascular permeability, proliferation, apoptosis, gene expression and migration; activation state of ERK1/2, affecting STAT phosphorylation and
cytokine responsiveness, in turn affecting vascular permeability, proliferation, apoptosis, gene expression and migration; tyrosine phosphorylation state of STAT3,
affecting cytokine induction. (2) illustrates the interaction of PECAM‐1 with Gai2, affecting Rho activation and cell motility and migration; (3) illustrates the modulation
of MMP‐2 & ‐9 expression by the presence of PECAM‐1 on the surface of endothelial cells via induction and nuclear targeting of GATA2 and p53 transcription factors;
(4) illustrates PECAM‐1's interactions with PI3K that modulates Akt activity, which in turn regulates Egr‐1 expression via p38 activation, leading to blunting of tissue
factor induction, reducing thrombosis, permeability and apoptosis in endothelial cells; illustrates PECAM‐1/PI3K interactions that also regulate GSK‐3beta activity via
Akt phosphorylation, resulting in blunting of beta catenin serine phsophorylation, reducing its proteosomal degradation; (5) illustrates tyrosine phosphorylated beta
catenin binding to PECAM‐1, resulting in sequestration of beta catenin, rendering it incapable of binding to VE‐cahderin, affecting junction formation; (6) illustrates the
binding of gamma catenin to exon 13 of PECAM‐1, dependent upon the phosphorylation state of PECAM‐1 residue S674.
The two differentiation pathways of human cytotrophoblasts. The key cell of the human placenta is the cytotrophoblast. These cells can follow two different
differentiation pathways: villous and extravillous (A). At the anchoring villi (B), the extravillous cytotrophoblasts (EVCT) are localized at the proximal column, proliferate,
and never express the human placenta lactogen (hPL). At the distal column, EVCT are invasive; these cells are detected by hPL immunolabeling (red). hPL labeling shows
EVCT migrating through the decidua, invading the spiral arteries, and replacing the endothelial cells (C). In the chorionic villi, villous cytotrophoblasts (VCT) fuse to form a
multinucleated syncytiotrophoblast (ST) (B) that covers the chorionic villi and expresses hPL. The ST has endocrine, exchange, and endothelial functions. dc, distal column;
dec, decidua; evct, extravillous cytotrophoblasts; m, mesenchyme; pc, proximal column; sa, spiral arteries; st, syncytiotrophoblast; vct, villous cytotrophoblasts.
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Hypothesis: Chemotaxis
Observation: cells migrate to higher concentrations of cells
S t ti f VEGF A di t i hibit
(Gamba et al. 2003; Serini et al., 2003)
• Saturation of VEGF‐A gradients inhibits
directional cell migration
• ECs produce VEGF‐A during first hour of vascular
development
Soluble Factors
Net, RUNX1, ets.1, FOXO4,
MEF2c, Elf‐1, COUP‐TFII, ESE‐1,
Smard3, Smad4, PPARQ, GAX,
HOXB3, KLF2, Fra‐1, ID, Egr‐1,
KLF5, VEZF1, JunD, Stat3,
NFAT, HANDI, c‐fos, Hey ½
Cell‐Surface
Receptor
NERF2, Elf‐1, Smad2, ID,
HOXA9, HOXB3, TFII‐IRD1, HEX,
KLF2, Egr‐1, TFII‐1, HAND2,
CREB, SCL/Tal‐1, Hey ½
Signaling Pathways
Nuclear receptors
P13K‐Akt pathway
PPARγ
All FOXO, SREBP, Notch1,
PPARγ
Transcription Fators
Cell survival/proliferation
differentiation, maturation
RUNX1, RUNX2,
HOX9, FOXO‐3a, FOXO4,
HDAC1, Egr‐1, c‐fos
Modulation of
inflammatory genes
GAX, PPARg, Egr‐1, C‐fos
Signaling Pathways/metabolism
RAS pathway Net, ets‐2
HIF‐1α degredation P
13K‐Akt pathway HDAC, FOXO4
Extracellular matrix
Vascular remodeling
COUP‐TFII, HOXD3, HOXA9,
HOXD10, HEX, ID, HOXA3,
RUNX2, FOXO1, Fra‐1, PPARγ
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Endogenous Inhibitors of Angiogenesis
Non‐Matrix Derived
Growth factors and cytokines
Interferons
Interleukins
PEDF
Platelet factor‐4
Other
Angiostatin
Antithrombin III(cleaved)
Chondromodulin
h d l
Matrix Derived
Arresten
Constatin
Collagen fragments
EFC‐XV
Endorepellin
Endostatin
Fibronectin fragments
Fibulin
Thrombospondin‐1 and ‐2
Nyberg, P. et al. Cancer Res 2005;65:3967‐3979
2‐Methoxyestradiol
PEX
Plasminogen Kringle 5
Prolactin fragments
Prothrombin Kringle 2
sFlt‐1
TIMPs
Troponin I
Vasostatin
Tumstatin
Ang1 signaling
1 19 80 263 283 498
S SCD CCD FReD
Ang‐1
L d i
Tie1/Tie2 Tie1/Tie2
Cytoplasm
Cytoplasm
Lg domain
EGF
repeat
FNII‐like
P P
P P
P
P
1102
1108
1102
1113
P P
?
Integrin
Tyrosine
Kinase
Brindle, N. P.J. et al. Circ Res 2006;98:1014‐1023
Cytoplasm
Cytoplasm
ShcA
P
Grb7 P13‐K SHP‐2
Grb2
Nck
Dok‐R ABIN2 Erk1/2
Akt
RhoA
NFkB
Pak1
FKHR
eNOS
FAK
Sprouting Motility Survival Migration Leukocyte adhesion
Anti‐permeability
1108 1113
?
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TGF-{beta} is a multifunctional regulator of cell proliferation and differentiation;
it regulates many different biological responses in a highly context-dependent manner
Bertolino, P. et al. Chest 2005;128:585S-590S
• Defisiensi plasentasi
• Defisiensi plasentasi
• Diamater < 40% Vs N
• Hertig : artherosis akut
• Hiperlipidemia
J Clin Invest 1997;99:2152-2164
Hypertens Pregnancy 1996;15:7-23
Br J Obstet Gynaecol 1986;93:1049-59
Am J Obstet Gynecol 1989;161:735-41
Am J Obstet Gynecol 1999;180:587-92
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Changes in serum endoglin
before onset of pre-eclampsia
Levine et al 2006
Candidate Placental Molecules for
Biomarkers
• sFlt‐1
• Endoglin
• PLGF
• VEGF
• Micro‐ and nano‐particles
Adverse actions on
endothelium and circulation
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Hipofisis
23 kDa Prolactin
Bromocriptine
16 kDa Prolactin
Cathepsin D
ROS
Cathepsin D
Gangguan Metabolisme
Sel Endothel
Apoptosis, disosiasi
kapiler, vasokonstriksi
oblast
Cell.2007;128, 589–600
STAT3 defisiensi
MnSOD
kapiler, vasokonstriksi
Gangguan mikrosirkulasi
Sel
Troph
PREEKLAMPSIA
Signal Transducers and Activators of Transcription (STATs)
