ANGIOGENESIS

Question 1

Aelius Galenus

Answer 1

theorized that venous blood is generated from the liver and then distributed to the rest of the body

Question 2

William Harvey

Answer 2

theorized the heart is a pump that recirculates blood out from the heart via arteries and back to the heart via veins

Question 3

Marcello Malpighi

Answer 3

discovered capillaries in chicken embryos and microtome (a microscopy tool)

Question 4

John Hunter

Answer 4

coined the term “angiogenesis”

Question 5

Wilhelm His

Answer 5

discovered endothelial cells

Question 6

Henryk Hoyer

Answer 6

discovered the lymphatic system

Question 7

Arthur Tremain Hertig

Answer 7

described angiogenesis in pregnant monkey placenta

Question 8

Judah Folkman

Answer 8

hypothesized tumor growth is dependent on angiogenesis

Question 9

Napoleone Ferrara Genentech

Answer 9

discovered VEGF

Question 10

Harold Dvorak

Answer 10

discovered VPF and as an identical protein to VEGF

Question 11

angiogenesis

Answer 11

formation of new blood vessels via extension or remodeling of existing capillaries
- an existing capillary –> multiple capillaries in the presence of growth factors like VEGF, Angiopoietin-2

Question 12

endothelial cells

Answer 12

epithelial cells of blood vessels that promote angiogenesis when stimulated by certain molecules; they are very reactive to their environment and thus are the gatekeepers of tumor cells

Question 13

Physiological angiogenesis

Answer 13

when there is a need for new blood vessel formation without pathology or disease; most prominent during embryonic development or during adulthood in wound healing, menstrual cycle and hair growth

Question 14

Pathological angiogenesis

Answer 14

impaired angiogenesis under diseased conditions, resulting in either increased or decreased sufficient angiogenesis
(i.e decreased angiogenesis in event of a heart attack or stroke)

Question 15

components of a blood vessel

Answer 15

tunica intima: endothelium
tunica media: internal elastic lamina, smooth muscle layer, external elastic lamina
tunica adventitia: adventitial CT

Question 16

Arteries

Answer 16

the pressure vessels for blood coming from the heart

Question 17

examples of large/elastic arteries

Answer 17

aorta, pulmonary artery

Question 18

examples of muscular/medium arteries

Answer 18

coronary and renal arteries (branches of aorta)

Question 19

examples of small arteries

Answer 19

arteries less than 2mm in diameter and small arterioles (20-100 micrometers)

Question 20

Veins

Answer 20

the capacitance vessels carrying blood from the tissues back to the heart; have all features of an artery but are thinner and contain less tissue

Question 21

capillaries

Answer 21

thin and fragile vessels optimal for gas exchange and diffusion of molecules; made up of only ONE endothelial cells with no media/smooth muscle layer

Question 22

continuous capillaries

Answer 22

have no openings d/t tight, non-permeable junctions in their walls and are lined continuously with the endothelial cell body

Question 23

fenestrated capillaries

Answer 23

have small openings (fenestrae) covered by a small diaphragm (connections of fibrils) to allow rapid passage of macromolecules; consists of a continuous basement membrane over the fenestrae

Question 24

discontinuous capillaries

Answer 24

have many fenestrations with no diaphragm, a large lumen and a discontinuous/absent basement membrane

Question 25

Functions of endothelial cells

Answer 25

1- provide inner lining to heart and blood vessels 2- secretion of bioactive molecules (i.e heparin, prostacyclin, etc) 3- modulation of blood flow and vascular reactivity 4- mediate angiogenesis and normal microvascular growth 5- regulation of inflammation and immunity 6- transport molecules from blood to interstitial fluid 7- interact with adjacent cells during growth and disease (i.e smooth muscle cells) 8- play a key role in pathological angiogenesis

Question 26

Factors leading to endothelial dysfunction

Answer 26

infection, injury/trauma, immunosuppressant drugs, hypoxia and oxidative stress, disease and aging, genetic risk factors, thrombosis, inflammation, cancer - all of these factors have negative interactions with endothelial cells and that interaction is what disturbs normal angiogenic processes

Question 27

Consequences of endothelial cell dysfunction

Answer 27

reduced NO, angiogenesis, increased vascular permeability (leakage), increased endothelial cell inflammatory response, increased leukocyte adhesion - if part of normal immune response, is okay - BUT angiogenesis should not be a regular function so this would result in a fully developed disease

Question 28

cytokine storm

Answer 28

exaggerated immune response resulting in the overproduction of cytokines which would then stimulate endothelial cells to commit to increased vascular permeability, secretion of molecules like thrombin and other inflammatory response mechanisms that would lead to endothelial cell dysfunction and eventually multiorgan failure

Question 29

How does the Angiotensin (AT) system regulate vasoconstriction?

Answer 29

ATII binds AT1R (a GPCR) on endothelial cell membrane, activating kinases like JAK, MAPK etc --> vasoconstriction, fibrotic modeling and inflammation

Question 30

How does the Angiotensin (AT) system regulate vasodilation?

Answer 30

1- ATII binds AT2R on endothelial cell membrane, activating PTPases like PTP, PP2A etc --> vasodilation and growth inhibition 2- AT and ATIII bind MAS R on endothelial cell membrane, activating molecules like Calcium, IP3, PLC --> vasodilation, anti-fibrosis and anti-inflammatory responses

Question 31

Turnover time for an endothelial cell

Answer 31

100 days - endothelial cells grow in 2D and 3D due to extracellular matrix proteins - proliferation past this is inhibited due to contact with the capillary basement membrane

Question 32

Vasculogenesis

Answer 32

de novo blood vessel development from vascular progenitor cells - angioblast progenitor (an immature, undifferentiated cell) --> capillary in the presence of growth factors like VEGF and bFGF

Question 33

Arteriogenesis

Answer 33

formation of mature blood vessels and differentiation into veins and arteries - existing capillary --> artery/vein phenotype with development of smooth muscle layer in the presence of growth factors like VEGF, Angiopoietin-1, PDGF - vessel is already predestined to become a specific vessel type

Question 34

Hemangioblasts

Answer 34

mesodermal-derived cells that are differentiated to hemangioblast cells in response to high concentrations of certain bone morphogenetic proteins - mesoderm cell --> hemangioblast --> angioblast --> endothelial cell (capillary)

Question 35

Angioblast

Answer 35

precursor cell of the vascular endothelial cells, derived from hemangioblast precursor cell

Question 36

First phase of vasculogenesis

Answer 36

mesodermal cells specified to become hemangioblasts aggregate into blood islands where the innermost cells become the hematopoietic stem cells and the outermost cells become the angioblasts

Question 37

blood islands

Answer 37

upon reaching a specific density, aggregates of hemangioblasts that condense to give rise to hematopoietic stem cells to become blood cells and angioblasts to become endothelial cells

Question 38

Second phase of vasculogenesis

Answer 38

angioblasts multiply and differentiate into endothelial cells

Question 39

Third phase of vasculogenesis

Answer 39

the endothelial cells form tubes and connect to form a network of capillaries called the primary capillary plexus

Question 40

Sprouting angiogenesis

Answer 40

the branching pattern of existing blood vessels to make a new blood vessel - vessel sprouts OUTWARDS

Question 41

Non-spouting angiogenesis

Answer 41

formation of blood vessels by a splitting process in which the existing capillary wall extends into the lumen to split the vessel in two - vessel sprouts INWARDS towards the lumen, resulting in formation of two vessels each with their own lumen - requires inter-endothelial contact

Question 42

stalk cells

Answer 42

endothelial cells that trail behind tip cells in growth and proliferation, undergo rearrangement for lumen formation

Question 43

tip cells

Answer 43

endothelial cells that grow and proliferate towards site of injury, in which two tip cells eventually fuse to create a lumen of a new blood vessel - lay down ECM for new vessel formation - also encourage stalk cells to grow as well

Question 44

filopodia

Answer 44

stimulated by VEGF and formed by tip cells that serve to guide subsequent tip cells in response to attractive and repulsive cues of vessel formation - regulated by Cdc42 and ephrinB2/VEGFR-2

Question 45

ACTIVATORS of angiogenesis

Answer 45

VEGF, SDF-1, Cxcl12, angiogenin, angiopoietin 1, basic fibroblast GF, interleukin 8, placental GF - encourage endothelial cells towards vessel formation

Question 46

INHIBITORS of angiogenesis

Answer 46

Seme3E, Netrin, Robo4, angiostatin, endostatin, interferon, itnerleukin 12 - discourage endothelial cells from vessel formation

Question 47

Robo4/UNC5b

Answer 47

signals to promote stabilization of the endothelial layer through inhibition

Question 48

Stalk cell stabilization

Answer 48

controlled by Notch activity fine-tuned by NRARP and SIRT1, enhancing connection of smooth muscle cells to stabilize the vessel

Question 49

Major regulator of angiogenesis

Answer 49

VEGF ligands - it is the binding/response of these ligands to VEGF that starts off angiogenesis

Question 50

Hypoxia-induced factor (HIF)

Answer 50

transcription factor that is stimulated to promote rapid gene production in the absence of oxygen HIF alpha binds HIF beta in the nucleus to promote further gene expression, promoting the expression of VEGF to stimulate angiogenesis - under normal oxygen conditions, HIF alpha binds pVHL which would ubiquinate/degrade the protein and angiogenesis would not occur

Question 51

Example anti-angiogenesis drugs

Answer 51

ziv-Aflibercept, Bevacizumab, Ramucirumab, Demcizumab