Cell Control Mechanisms: Cellular Aggregation and Adhesion

Dr. McNamara
I. Shear Stress
a. Pressure-induced force b/w 2 laminae
b. At wall surface: greatest shear rate and least velocity
c. At vessel center: gretest velocity and least shear rate
d. Causes NO release
II. Blood Vessel Wall
a. Tunica adventitia
i. outer layer, surround the tunica media
ii. connective tissues, prevents ballooning of vessel with high
systolic BP.
iii. Aneurysm is caused by weakness of adventitia
b. Tunica intermedia
i. Surrounds tunica intima (middle layer)
ii. Smooth muscle involuntary constriction and dilation
iii. Connective tissue collagen fibers whose elasticity is reduced
by hypertenstion.
c. Tunica Intima
i. Endothelium innermost layer of cells that separate the
remainder of the vessel from the lumen.
ii. Basement membrane thin layer of spongy connective tissue
that secretes elastic collagen.
d.
III. Hemostasis
a. Process by which blood is maintained in the fluid state.
b. Components
i. Platelets involved in primary hemostasis
ii. Coagulation system involved in 2ndary hemostasis
iii. Fibrinolytic system
iv. Inflammatory process
v. Wound healing process
c. Primary
i. 1
st
response to vascular injury
ii. Mechanism
1. Activation of platelets via thrombin (thromboxane)
2. Adhesion of platelets b/w GP(glycoprotein)Ib and VWF
(von Willebrand Factor)
3. release of platelet granule products to recruit more
platelets to site of injury
4. aggregation of platelets via interaction b/w GPIIb/IIIa
and fibrinogen
iii. triggers 2ndary hemostasis (coagulation proteins)
d. Secondary process of coagulation
i. Mechanism
1. coagulation proteins generate thrombin
2. thrombin converts fibrinogen to fibrin
3. fibrin consolidates the platelet plug made in primary
hemostasis forming a thrombus
ii. prevents further blood loss form injury site
IV. Platelet
a. Structure
i. Disk-shaped, anuclear
ii. GPIb involved in adhesion
iii. GPIIb/IIIa is primary receptor for fibrinogen
iv. Provides procoagulant surface for coagulant proteins to
interact.
v.
b. Mechanisms of participation in hemostasis
i. Adhesion
ii. Secretion
iii. Aggregation
iv. Coagulation (provide procoagulant surface)
v. Clot retraction
V. Procoagulant Surface of the Platelet
a. VWF anchors to platelet at GPIb and to exposed collagen of injury site,
= adehesion.
b. Fibrinogen binds to GPIIb/IIIa receptors of 2 platelets producing
aggregation.
c. Activation of the platelet causes changes in the cell membrane charge
producing the procoagulant surface.
d. Pro-thrombin complex (FXa/FVa) converts pro-thrombin (FII) to
Thrombin (FIIa)
VI. Thrombus Formation
a. Initiation platelets tether and adhere to a site of vascular injury
b. Propagation
i. Platelets become activated
ii. More platelets are recruited to the site and aggregate
c. Thrombus Stabalization
d. Summary - tethering => activation => aggregation => stabalization.
VII. Cell Adhesion
a. The way cells talk to each other
b. Important for:
i. Tissue formation during morphogenesis
ii. Cell migration
iii. Regulation of : cell proliferation, gene expression and cell death
(apoptosis)
VIII. Leukocyte Adhesion Cascade
a. 5 steps
i. Capture P-selectin is primary selectin for capture and
initiation of rolling
ii. Rolling P-selectin is most important
iii. Slow rolling E-selectin is most important
iv. Firm adhesion E-selectin is responsible for conversion of
slow rolling to firm adhesion. CD18 integrins are responsible
for the deceleration of leukocytes.
v. Transmigration occurs if exogenous chemoattractants are
present.
b. 3 major stages
i. Dilation of capillaries to increase blood flow
ii. Microvascular structural changes and escape of plasma
proteins from the bloodstream
iii. Leukocyte transmigration through endothelium and
accumulation at the site of injury.
c. Selectins
i. Transmembrane molecules expressed on the surface of
leukocytes and activated endothelial cells.
ii. Initial attachment of leukocytes during inflammation via
transient, reversible and adhesive interactions called leukocyte
rolling.
iii. 3 types
1. L-selectin smallest, found on leukocytes
2. P-selectin largest, found on activated platelets and
endothelial cells.
3. E-selectin found on activated endothelium
d. Integrins
i. Heterodimeric transmembrane glycoproteins that attach cells
to the extracellular matrix proteins of the basement membrane
or to ligands on other cells.
ii. Structure
1. Large () subunits
2. Small () subunits
iii. Leukocyte integrins:
1. 2 or CD18 integrins
2. most important member is Very Late Antigen 4 (VLA4)
which is responsible for leukocyte adhesion to vascular
endothelium and leukocyte recruitment to the inflamed
area.