Angiogenesis

Question 1

Stimulation of angiogenesis

Answer 1

Stim by hypoxia

Question 2

Angiogenesis pathway

Answer 2

Hypoxia to hypoxia induced factor (HIF)=TF, constant low levels and degraded. Induces VEGF which binds to VEGFR (RTK) in nearby endo cells (induces MAPK) leading to chemotaxis towards angiogenic stim, endo cell prolif, diff, secrete proteases and migrate (integrins) leading to increased perm and finally increases migration, nutrients, and plasma proteins

Question 3

Process of angiogenesis

Answer 3

VE cells stimulated by binding of proangiogenic GFs to GFR. VEGF vasodil and increases perm. MMP release leads to BM degrade and reduced cell-cell adhesion

Question 4

MMPs: ECM degrade

Answer 4

Matrix metalloproteinases = collagenase (type 4), regulated by TIMPs (proteinase inhibs). MMPs stored in ECM/confined to cell surface receptors, action confined to specific areas via TIMPs

Question 5

Reg of angiogenesis

Answer 5

activators = VEGF and FGF
Inhibs = thrombospondin, INF alpha and beta, angiostatin, endostatin

Question 6

Beginning of angiogenesis

Answer 6

Decreased oxygen leads to HIF to hypoxia response element (HRE) to transC of proangio factors (VEGF and bFGF)

Question 7

Reg of HIF-1

Answer 7

by pVHL. Normoxia proline hydroxylases adds OH to HIF-1. HIF-OH binds pVHL therefore triggering HIF ubiq.

No oxygen means no OH therefore it can dimerize and activate

Question 8

von Hippel Lindau Syndrome

Answer 8

AD, VHL=ubiq ligase subunit. Inherited cancer syndrome with multi-hemangioblastomas of CNS and retina. Increased HIF-1 regardless of oxygen available leads to increased VEGF

Question 9

Hemangioma

Answer 9

abnormal dense collection of dilated capillaries. Children and FMs. Increased VEGF and FGF; decreased TNFB,TGFB,IFNgamma

Superficial strawberry nevus on skin = benign lesions

Question 10

Tumor angiogenesis

Answer 10

Solid tumor growth, can’t grow more than 2 mm without oxygen and nutrients and center is often necrotic. (inhib angio and tumor shrinks and dormant). Dramatically increases metastatic potential

Question 11

Targeting angiogenesis

Answer 11

Vegf inhib by Bevacizumab; VEGFR inhib by Sunitinib, Serafinib

Question 12

Anti angio strats

Answer 12

Inhib proangio factors with mabs (VEGF); inhib MMPs and increase TIMPs

Question 13

Endogenous anti-angio factors

Answer 13

Angiostatin (plasminogen fragment that induces apop). ECM derived = thrombospondin, endostatin (coll 18), tumistatin (coll 4)

Question 14

Thrombospondin

Answer 14

Recently formed endothelial cells have FAS present, Tsp induces expression of FasL leading to apop

Question 15

Endostatin

Answer 15

Stabilizes newly formed blood vessel walls creating anchors and therefore inhib new vessel sprouting