Lecture 5: Vascular Biology Flashcards Preview

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Flashcards in Lecture 5: Vascular Biology Deck (39):

Where is flow fastest? Slowest?

In the middle of the vessel
Along the endothelium


What is the difference between laminar and turbulent flow?

Laminar is all in one direction
Turbulent can go in different direction pg. 5 of ppt


What is shear stress? Significance?

Friction between layers of fluids sliding over each other
These forces affect endothelial function
Endothelial cell can change its morphology based on sheer stress


What is rheology?

The study of the flow of matter, primarily in the liquid state


What is an example of hyperemia?

Dilation of the artery that lasts for 10 minutes AFTER application of a blood pressure cuff


What are conduit arteries?

The highways (aorta)
Carries shit directly from one place to another


What are the 4 roles of the endothelium?

1. Modulates TONE
2. Modulates GROWTH
3. Modulates HEMOSTASIS
Endothelium is the business end of the CV system


How does endothelium vasodilate?

1. NO (aka endothelial derived relaxing factor or EDRF)
2. Prostacyclin (PG12)
3. Bradykinin
4. Acetylcholine
Therefore you need an INTACT endothelium to vasodilate


What is endothelial derived relaxing factor?

Nitric oxide


True or false, an intact endothelium is necessary for vasodilation?



How is NO synthesized?

Synthesized from L-arginine by NO synthase (eNOS or NOS III from endothelial cell)
Enzyme is stimulated by blood flow across the endothelial cell surface (shear stress) or by chemical mediators like Ach


What is the MoA of NO?

NO diffuses to underlying smooth muscle cells
NO stimulates GUANYLATE CYCLASE and generates cGMP
cGMP will cause SMC to relax
Substance P, bradykinin, ACh and B-agonists regulate NO


What are the two roles of Ach? What accounts for this pseudoparadox?

Ach can vasodilate AND vasoconstrict
Ach can vasodilate by interacting with the Ca-calmodulin pathway within the ENDOTHELIAL cell to promote NO synthesis
ACh can vasoconstrict by acting DIRECTLY on the smooth muscle cell


Significance of roles of Ach in vasoconstriction/dilation?

If arteries vasodilate, endothelial cells intact
If arteries vasoconstrict, endothelial cells are damaged so NO diffuses directly to smooth muscle cells
So if coronary vessels vasoconstrict with ACh, then you know that there is atherosclerotic damage


What are the key features of NO?

A gas released by endothelium
Release stimulated by
i. shear stress
ii. physiologic agonists
iii. pathologic insults
Inhibits platelet activation, secretion and aggregation; maintains vascular relaxation
Low levels of NO maintain vessel in state of dilation in normal state


What are key features of prostacyclin?

Released by endothelium
Release stimulated by
i. shear stress
ii. physiologic agonists
iii. pathologic insults
Inhibits platelet activation, secretion and aggregation; maintains vascular relaxation
Antithrombotic and relaxation properties potentiated by nitric oxide


What is the role of ACE in modulating bradykinin?

ACE inhibits the biologic effects of bradykinin by cleaving two of its carboxy terminal peptides
Significance = breakdown products of bradykinin lead to release of NO and PGI2
Release of NO and PGI2 = vasodilation
ACE also makes angiotensin II which is a vasoconstrictor so it has opposite roles


What do fat meals do to vascular circulation?

Higher fat meal = less vasodilation
Less circulation


What factors lead to vasoconstriction?

1. Endothelin
2. Angiotensin II
3. Thromboxane A2 (produced by cyclooxygenase and its production is inhibited by aspirin)
4. Acetylcholine
5. superoxide (free radical O2)


Why does controlling vascular growth matter?

1. growth factors involved in normal vascular growth and development in utero and after birth
2. important for adequate response to injury
-fracture healing
-vascular ischemia due to vessel obstruction
3. Pathologic growth of blood vessels can occur
-benign or malignant tumors
-diabetic retinopathy


How does vessel growth occur?

1. specification
2. vasculogenesis
3. angiogenesis


What does the endothelium produce that is involved in vessel growth?

2. fibroblast growth factor
4. endothelin
5. angiotensin II


What are EPCs?

Endothelial Progenitor Cells
e.g. VEGF
Very important for recovery from injury or insult
Vascular damage can lead to less EPC migration


What are the key characteristics of Hereditary Hemorrhagic Telangiectasia (HHT)?

Autosomal dominant vascular anomaly
TGF-Beta signaling is disrupted in these individuals, leading to aberrant vessel growth
Presence of multiple small telangiectases of the skin, mucous membranes, GI tract
Associated with recurrent episodes of bleeding and gross/occult melena


What are the symptoms of Hereditary Hemorrhagic Telangiectasia (HHT)?

Bleeding in GI tract
Arteriovenous malformations in lung causing shunting of blood and paradoxical emboli
Infection from septic emboli
Aka Osler-Weber-Rendu (OWR)


What are the anti-clot factors?

1. Fibrinolytic-tissue plasminogen activator (tPA)
2. anti-thrombin = thrombomodulin and Heparin
3. Antiplatelet
i. NO
ii. Prostacyclin
iii. ADPases


What are the pro-clot factors?

1. Anti-ifibrinolytic plasminogen activator inhibitor -1 (PAI-1)
2. Angiotensin II stimulates PAI-1


How does endothelium maintain blood fluidity?

Releases factors (like tPA) that makes blood fluid
NO ENDOTHELIUM = potential clot that cannot be lysed


Why do ADPases promote anti-clotting?

Because ADP is secreted by platelets to promote platelet adhesion
Cleaving ADP thereby decreases platelet adhesion


What is Virchow triad?

1. Hypercoagulable state
2. Circulatory Stasis
3. Endothelial injury
Perfect confluence of events that lead to clotting


What are the PROcoagulation properties of dysfunctional endothelium?

1. increases vWF factor production with increased platelet adhesion and aggregion
2. Increases synthesis of plasminogen activator inhibitor I (PAI-1) resulting in impaired fibrinolysis


What are red thrombi?

Thrombi that form in veins
Formed of predominately red cells


What are white thrombi?

Thrombi that form in arteries
Formed primarily of white cells


What are the adhesion molecules expressed on the endothelium?

Cell Adhesion Molecules (CAM) which include ICAM-I and VCAM-1


How does angiotensin II lead to atherosclerosis?

1. promotes VCAM-1 formation in endothelial cell to promote monocyte adhesion
2. stimulates NFkB which leads to formation of MCP-1 which leads to monocyte recruitment
3. stimulates smooth muscle cell to form IL-6 which leads to inflammatory marker C-reactive protein (CRP)


What are the characteristics of Vascular cell adhesion molecule-1 (VCAM-1)?

1. binds monocytes and lymphocytes in atheroma
2. expressed by endothelium over fatty streaks
3. expressed by microvessels of mature atheroma


What is an atheroma?

A swelling of the vessels due to accumulation of macrophages


What is insudation?

The accumulation, as in the kidney, of a substance derived from blood


What are the key factors that lead to the formation of atherosclerosis?

1. Endothelial dysfunction
2. Chronic inflammation
3. genetic predisposition
4. Environmental factors
As caused by
i. lipids
ii. tobacco
iii. hypertension
iv. Diabetes mellitus