8 angiogenesis Flashcards
What is angiogenesis?
The growth of new blood vessels from the existing vasculature.
Why is angiogenesis important?
It plays a key role in normal physiological processes (development, wound healing, reproduction) and in diseases like cancer and chronic inflammation.
What is the difference between vasculogenesis and angiogenesis?
Vasculogenesis: Formation of blood vessels from mesoderm-derived angioblasts.
Angiogenesis: Formation of blood vessels from pre-existing vasculature.
How does angiogenesis occur in adults?
Normally quiescent endothelial cells (ECs) can be rapidly activated under specific conditions.
What are the 10 key steps in the angiogenic cascade?
Angiogenic factor production
Release
EC receptor binding
EC activation (BM degradation)
EC proliferation
Directional migration
ECM remodelling (MMPs)
Tube formation
Loop formation
Vascular stabilisation (SMC and pericyte recruitment)
What triggers endothelial cell activation?
Binding of angiogenic factors (e.g., VEGF) to their receptors.
What happens after endothelial cells are activated?
They release proteases, migrate, proliferate, and differentiate to form new vessels.
What are the main endothelial cell surface receptors involved in angiogenesis?
VEGFR-1, VEGFR-2, VEGFR-3, TIE-2
List physiological processes that require angiogenesis.
Embryonic development, wound healing, reproductive cycles (menstrual cycle, ovulation, placenta formation).
List pathological conditions associated with angiogenesis.
Tumour growth, rheumatoid arthritis, diabetic retinopathy, psoriasis.
Why is angiogenesis critical for tumour growth?
Tumours cannot grow beyond 1-2 mm³ without a blood supply.
How do tumours induce angiogenesis?
Hypoxia triggers VEGF production, stimulating blood vessel formation.
How does tumour vasculature differ from normal blood vessels?
Up to 10% of tumour-associated endothelial cells are proliferating at any time.
What determines whether angiogenesis occurs?
A balance between angiogenic promoters and angiogenic inhibitors.
List key positive regulators of angiogenesis.
VEGF, FGF, PDGF, EGF, Angiopoietin-1, TGF-β.
List key negative regulators of angiogenesis.
Thrombospondin-1, Angiostatin, Endostatin, TIMPs, Tumstatin, Interferon-α.
How do TIMPs regulate angiogenesis?
They inhibit MMPs, preventing ECM degradation and endothelial invasion.
What happens if the balance between MMPs and TIMPs is disrupted?
Excess MMP activity promotes tumour angiogenesis; excess TIMP activity inhibits it.
Which microenvironmental factors influence angiogenesis?
Proteolytic enzymes, growth factors, hypoxia, cell adhesion molecules.
How does hypoxia promote angiogenesis?
It stabilises HIF-1α, leading to VEGF production.
What metabolic changes occur due to hypoxia?
Increased glycolysis (via LDH-A), increased glucose uptake (GLUT1), reduced TCA cycle activity (PDK1).
Which transcription factor plays a major role in hypoxia-induced angiogenesis?
Hypoxia-Inducible Factor-1 (HIF-1).
How does the tumour microenvironment trigger the “angiogenic switch”?
Low pH, low nutrients, high interstitial pressure, and low oxygen levels trigger VEGF production.
What are the major families of angiogenic growth factors?
VEGF, FGF, PDGF, TGF-β, EGF.
What is the function of VEGF-A?
Stimulates matrix breakdown, EC migration, proliferation, capillary tube formation, and vascular permeability.
How is VEGF-A regulated?
By oxygen tension (hypoxia-inducible factors, HIF-1) and other growth factors (EGF, FGF, TGF-α).
Which VEGF receptor is the main driver of angiogenesis?
VEGFR-2 (stimulates EC proliferation and migration).
Which VEGF receptor is mostly antagonistic to angiogenesis?
VEGFR-1 (inhibits VEGFR-2 activity, but recruits macrophages).
What role do TIE-2 receptors play in angiogenesis?
TIE-2 and Angiopoietin-1 stabilise newly formed blood vessels.
Which enzymes remodel the ECM during angiogenesis?
Matrix Metalloproteinases (MMPs) and Plasminogen Activators (PAs).
What is the role of MMPs in angiogenesis?
Degrade ECM components, release sequestered growth factors, regulate EC attachment and migration.
What are the key inhibitors of MMPs?
Tissue Inhibitors of Metalloproteinases (TIMPs).
Why is tumour angiogenesis an important drug target?
Blocking tumour blood supply can starve the tumour of oxygen and nutrients.
What challenges exist in delivering drugs to solid tumours?
Abnormal blood flow, high interstitial pressure, poor lymphatic drainage
What is an example of an anti-angiogenic drug?
Bevacizumab (Avastin) – a monoclonal antibody against VEGF.
How do integrin inhibitors target angiogenesis?
αvβ3 antagonists block pathological angiogenesis with minimal effects on normal vasculature.
Which drug inhibits MET, AXL, and VEGF receptors?
Cabozantinib – used in metastatic castration-resistant prostate cancer (mCRPC).
What are the benefits of targeting tumour-associated endothelial cells?
Affects both primary tumours and metastases, reducing the chance of recurrence.
What does Cabozantinib target?
inhibits MET, AXL and VEGF receptors
How does HIF-1 regulate metastasis?
It promotes EMT, immune evasion, and treatment resistance.
Which metabolic adaptation helps colon cancer cells survive hypoxia?
Increased expression of Creatine Kinase Brain-Type (CKB) to regulate ATP stores.
What role do integrins play in angiogenesis?
Mediate cell adhesion, EC migration, and angiogenic signalling.
What does VEGFR inhibition cause?
Reduced tumour vascularisation, increased hypoxia, and tumour cell death.
Which receptor is targeted by the drug Vitaxin?
αvβ3 integrin.
What is the main angiogenic factor secreted by tumours?
VEGF-A.
What is the role of nitric oxide in angiogenesis?
Promotes vasodilation and blood vessel formation.
Why do tumours develop abnormal vasculature?
Imbalanced VEGF signalling leads to disorganised and leaky vessels.
What is the key marker of angiogenic endothelial cells?
CD31 (PECAM-1).
What enzyme stabilises HIF-1 under hypoxia?
Prolyl hydroxylase inhibition prevents HIF-1 degradation.
Which cancer has the highest angiogenic activity?
Glioblastoma
Glioblastoma.
What is a common side effect of anti-angiogenic therapy
Hypertension due to reduced vascular permeability.
VEGF Signalling Pathway
EGF binds to VEGFR-2 on endothelial cells (ECs), triggering receptor dimerization.
This activates intracellular tyrosine kinase domains, leading to phosphorylation cascades.
Downstream signalling pathways include:
MAPK pathway → EC proliferation.
PI3K/Akt pathway → EC survival and migration.
PLCγ pathway → Increased vascular permeability.
Role of VEGFR-1 vs VEGFR-2
VEGFR-2 (Flk-1/KDR): Primary driver of angiogenesis, promoting EC proliferation and migration.
VEGFR-1 (Flt-1): Acts as a “decoy” receptor, limiting excessive VEGF signalling. However, it also recruits macrophages, which release angiogenic factors.
How Proteolytic Enzymes Enable Angiogenesis
MMPs (e.g., MMP-2, MMP-9) degrade the basement membrane, allowing ECs to invade tissues.
Plasminogen activators (PAs) convert plasminogen to plasmin, which breaks down fibrin and ECM components.
This releases growth factors like VEGF stored in the ECM, amplifying angiogenesis.
The Angiogenic Switch in Tumours
When tumours outgrow their blood supply, hypoxia triggers HIF-1α stabilization.
HIF-1α upregulates VEGF, FGF, and other angiogenic factors.
This leads to the recruitment of bone marrow-derived endothelial progenitor cells (EPCs) that aid vessel formation.
. Role of Integrins in Angiogenesis
αvβ3 and αvβ5 integrins promote EC adhesion and migration.
These integrins interact with the ECM and regulate VEGF signalling.
Blocking αvβ3 with monoclonal antibodies (e.g., Vitaxin) can inhibit tumour angiogenesis.
Hypoxia-Induced Metabolic Reprogramming
In low oxygen, tumours shift from oxidative phosphorylation to glycolysis.
HIF-1α upregulates LDH-A, increasing lactate production.
This promotes an acidic microenvironment, further stimulating angiogenesis via VEGF release.
Anti-Angiogenic Drug Mechanisms
Bevacizumab (Avastin): A monoclonal antibody targeting VEGF, preventing it from binding VEGFR-2.
Sunitinib & Sorafenib: Inhibit multiple tyrosine kinases, including VEGFR and PDGFR.
Thalidomide: Downregulates VEGF and FGF, disrupting tumour blood supply.
Mechanisms of Resistance to Anti-Angiogenic Therapy
Tumours upregulate alternative angiogenic factors (e.g., FGF, HGF) when VEGF is blocked.
Increased pericyte coverage stabilizes vessels, making them resistant to therapy.
Tumour cells use vessel co-option, where they hijack existing blood vessels instead of forming new ones.
Role of Pericytes in Vascular Stabilisation
Pericytes wrap around endothelial cells, reducing vessel permeability.
They are recruited via PDGF-BB and Angiopoietin-1 (ANGPT1) signalling.
Loss of pericytes (e.g., via PDGFR inhibitors) leads to leaky, dysfunctional vessels.
Therapeutic Targeting of the Tumour Microenvironment
Combining anti-angiogenic therapy with immune checkpoint inhibitors can enhance tumour response.
Normalising tumour vasculature (rather than destroying it) may improve drug delivery and immune infiltration.
Starving the tumour of nutrients (e.g., glucose restriction strategies) can work alongside angiogenesis inhibition.
