4. Angiogenesis

Define vasculogenesis

De novo blood vessel development from vascular progenitor cells

Layers of a blood vessel from lumen outward

Tunica intima, Tunic media, Tunica adventitia

What is the most important growth factor in the development of endothelial cells?

VEGF

Pathological angiogenesis

can be LACK of angiogenesis or EXCESS angiogenesis ex: age related macula degeneration (too much angiogenesis leading to vision loss)

Explain "Tumor-associated angiogenesis is not normal angiogenesis"

diseased conditions=disorganized, leaky, premature blood vessels. -this is problematic, because when giving a drug to a cancer patient, these drugs dont work because blood vessels are so mediocore, they cannot delicer these drugs directly to the site of the tumor... -drug goes to other areas causing SIDE EFFECTS

Experimental evidence for the role of angiogenesis in cancer: Tumors subcutaneously implanted into mice grow slowly before vascularization, and tumor volume increases ___________. After vascularization, tumor growth is rapid and tumor volume increases ________

linearly, exponentially

_______ are another word for pericytes, which are closely associated with endothelial cells in the microvasculature.

mural cells

New approach to angiogenesis cancer treatment?

new idea emerging. old idea: block blood vessels to treat cancer now: normalization--if you are able to make blood vessels look normal, and then do chemo to find tumor, you should have effective treatment. Now need to figure out what dosage and what time... not trying to get rid of blood vessels but to reduce them and look more normal and THEN give anti-cancer drugs.

In pathological circumstances, lack of oxygen, HIF-alpha transcription factor is not degradated by ______ because it is inhibited by ________-preventing HIF-alpha from interacting with pVHL. -HIF-alpha stimulates the expression of _______--stimulating angiogenesis

pVHL, S-nitrosylation, VEGF

Where are continuous capillaries found?

skeletal muscle, heart, lung, and brain

Define fenestrated capillaries

small openings called fenestrae (about 80-100nm in diameter). Fenestrae are covered by a small non-membranous permeable diaphram allowing passage of macromolecules. Found in endocrine glands, intestinal villi, and kidney glomeruli

Experiments show that ________ supports tumor growth

stroma

Define continuous capillaries

they have no openings (tight non-permeable junctions) in their walls. Found in skeletal muscle, heart, lung, and brain

What is non-sprouting angiogenesis?

-Re-modeling of existing vessels - Inter-endothelial contact is needed - Splits into two vessels.

Endothelial cells respond to environmental stimuli. Some activators of endothelial cells include:

-cytokines, growth factors, lipids' -infectious agents (bacteria/virus) -hemodynamic forces -environmental stress

Three types of capillaries

1. Continuous 2. Fenestrated 3. Discontinuous

Examples of physiological angiogenesis

1. Embryonic development (vasculogenesis) 2. Adulthood: wound healing, menstrual cycle, and hair growth

What are the two types of angiogenesis?

1. Sprouting angiogenesis (most common) 2. Non sprouting/intusseceptive angiogenesis

Two major strategies for inhibiting VEGF signaling

1. block function of VEGF interacting w/ receptor 2. target enzymatic activity of receptors (kinase tyrosines)

Basic steps of sprouting angiogenesis 1. increase in vessel ____________ in response to VEGF 2. Loosening of __________ contact 3. Enzymatic degradation of capillary ______________ 4. Endothelial cell ____________ 5. Directed ___________ of endothelial cells. 6. Sprouting/_______________ (EC tube formation) 7. Endothelial cells start to adhere to each other and make a _______. 8. ___________ are attached to endothelial cells. 9. Finally, blood vessels sprouts will _______ with other sprouts

1. permeability 2. pericyte 3. basement membrane 4. proliferation 5. migration 6. tubulogenesis 7. lumen 8. pericytes 9. fuse

What is the turnover time for an endothelial cell?

100 days

In vasculogenesis, capillaries are formed from vascular progenitor cells called ____________.

Angioblasts. Angioblasts response to growth factors VEGF to form a capillary.

What is phase two of vasculogensis?

Anioglasts multiple and differentiate into endothelial cells.

Phase 1 of vasculogenesis: Hemangioblasts (from mesoderm) condense into aggregations that are called ____________. The inner cells become_________ and the outer cells become_________.

Blood island, hematopoeitic stem cells, angioblasts

Proliferation of endothelial cells is inhibited due to contact with the _____________________.

Capillary basement membrane

Third phase of vasculogensis?

Enothelial cells form TUBES and connect to form the PRIMARY CAPILLARY PLEXUS, a network of capillaries

Arteriogenesis

Formation of mature blood vessels; differentiation into veins and arteries

Define angiogenesis

Formation of new blood vessels via extension or remodeling from existing capillaries

In normoxia __________ (transcription factor) is usually bound to _________ (protein) under normal circumstances, recognized by UB (ubiquinization) and highly degradated.

HIF-alpha, pVHL

_______________ are derived from mesodermal cells. They give rise to two cell types

Hemangioblasts 1. Angioblasts (which form endotheial cells) 2. Hematopoietic cells

What is the anti-angiogensis cancer therapy hypothesis?

Hypothesis: if blood vessels responsible for growing tumor, and you can target the angiogenesis you can shrink tumor and cure cancer. - but.... turns out doesnt work.

What controls expression of VEGF?

Hypoxia

Where are disontinuous capillaries found?

Liver, spleen, and bone marrow

Stalk cell stabilization relies on ________activity that is fine-tuned by NRARP and SIRT1. ______ and Notch intersect via NRARP and Lef1/ß-catenin to stabilize connections.

NOTCH, Wnt

Contact between mural cells and endothelial cells that are expressing the _______ ligand Jagged1 induces expression of both the Notch3 receptor and Jagged1 in mural cells. Upregulation of notch signaling in mural cells is associated with increased expression of SMC differentiation marker genes indicative of a maturation response by the mural cell.

NOtch

Define discontinuous capillaries

Open spaces between endothelial cells, very permeable. have a large lumen, many fenestrations with no diaphragm and a discontinuous or absent basal lamina. Found in liver, spleen and bone marrow

Order of cell types in vasculogenesis

Stem cells-->mesoderm-->Hemangioblast-->Angioblast---> Endotheial cells

____ cells are the "risk taker cells, as they are the first to start migrating towards the stimulant which is _________. _____ cells are the followers. They continue proliferating and fill the gap.

Tip, VEGF, stalk

Filapodia formation is regulated by_______ and ________ when they -need to put a stop to this process=_______________

activation, repulsion, endocytosis

Where are fenestrated capillaries found?

endocrine glands, intestinal villi, and kidney glomeruli

___________________ are one the most quiescent and genetically stable cells of the body.

endothelial cells

Migrating cells produce ______________: Most important molecule for formation is _________, also fibroblast growth factor . Filapodia ead tip cells whih sense an dfollow attractive and repulisve cue.

fillapodia, vegf

Possible explanation for why anti-angiogenesis cancer therapies are not effective

two diverse views: 1. adaptive resistance -when block VEGF, tumor cells rely on other factors to promote angiogenesis (when you block one pathway tumors use other pathways) 2. intrinsic non-responsiveness -tumors can use other pathways to create tumor - (all driven by observation, not clear which is which).