Cell Biology of Cardiovascular System

Question 1

Explain the gross structure of a blood vessel and why it differs in different blood vessels

Answer 1

Outermost layer is tunica adventitia, then external elastic lamina, then tunica media, then internal elastic lamina, then tunica intima (endothelium). The proportions in each layer differ depending on the type of blood vessel. Veins are thinner and less muscular than arteries. Muscular media layer present in large quantities in bigger vessels, disappearing as the vascular tree branches out until capillaries are just endothelia.

Question 2

Describe the main functions of the endothelia (tunica intima)

Answer 2

Regulate vascular tone
Barrier function - fluid and nutrient exchange regulation
Inflammatory response - regulation of blood cell trafficking to injury
Thrombosis
Angiogenesis

Question 3

Explain the different structures of endothelia and how they relate to their function

Answer 3

In vitro and in small vessels, endothelia have a cobblestone morphology where they are adhered to eachother and have a round shape. In vessels with stronger blood flow (larger) the cells have a flattened elongated shape which mimics the direction of flow, reducing the mechanical forces that act on them and hence reducing the risk of vascular injury. Also, the cells overlap to increase junctional area and strengthen barrier function

Question 4

Which different stimuli do endothelia respond to and list some responses

Answer 4

They respond to changes in O2 tension, blood flow, cicrculating cytokines and GFs by synthesising/excreting active vasomediators like endothelin-1, norepinephrine, angiotensin-1, thromboxane, prostacyclin, endothelial-derived relaxing factor NO. This communicates info about the external environment to smooth muscle in order to regulate tone and maintain vascular homeostasis

Question 5

What is the main function of the tunica media?

Answer 5

Regulation of vascular tone ie. constriction/relaxation. It can be endothelium dependent/independent.

Question 6

Describe the structure of the tunica media and how it relates to its function

Answer 6

Vascular smooth muscle encased in a collagen and elastin mesh - internal elastic lamina which separates it from the intima and forms a scaffold for muscle cells which contributes to strength and compliance.

Question 7

Describe the structure of the aorta and pulmonary artery in regards to media and how it relates to its function

Answer 7

The aorta has abundant collagen and elastin to support its many layers of smooth muscle cells - allowing it to withstand arterial pressure. The pulmonary artery has less smooth muscle and more elastin so it can deal with large changes in vol. without much change in pressure

Question 8

Describe the stucture and function of tunica adventitia

Answer 8

Consists of collagen, elastin, and other ECM interspersed with fibroblasts. Separated from media by external elastic lamina, which along with adventitia gives the vessel compliance

Question 9

Describe the differences in structure between aorta and pulmonary artery in regards to adventitia

Answer 9

Aorta has a thick adventitia with modest elastin:collagen, and it’s not very compliant. Pulmonary artery has thick adventitia with high elastin:collagen so is compliant.

Question 10

Describe the mechanism of action of Nitric Oxide

Answer 10

Vasorelaxant. Shear stress, increased O2, ventilation increase endothelial NO synthase activation which transforms L-arginine to L-citrulline and NO, which then goes into the smooth muscle and inhibits prolif, inflammation, and platelet adhesion. NO acts on soluble guanylate cyclase turning GTP to cGMP and leading to relaxation. Phosphodiesterase breaks down cGMP.

Question 11

Describe the mechanism of action of prostacyclin (PGI2)

Answer 11

Vasorelaxant. Endothelia and smooth muscle produce PGI2 via COX enzymes (from arachidonic acid). This acts via IP receptor to activate Adenylyl Cyclase which turns ATP to cAMP which induces relaxation. Phosphodiesterase breaks down cAMP. PGI2 also activates K channels which leads to increased K efflux leading to hyperpolarisation and closing of calcium channels which means no calcium inside which is needed for contraction - indirect relaxation.

Question 12

Describe the mechanism of action of Natriuretic peptides

Answer 12

ANP produced by heart (atrial), BNP by brain, and CNP (cellular) by brain, endothelia, chondrocytes. ANP release triggered by atrial and ventricular distention as well as neurohumoral stimuli usually in response to heart failure. They bind to particulate (membrane bound) Guanylyl Cyclase and convert to cGMP in smooth muscle which leads to relaxation. NO via soluble GC so effects can be additive.

Question 13

Describe the mechanism of action of Endothelin-1

Answer 13

ET-1 acts on ET-B receptors on endothelial cells to result in PGI2 and NO which lead to vasodilation. ET-B receptors on smooth muscle cells leads to vasoconstriction. ET-A on smooth muscle leads to vasoconstriction and proliferation. ET-1 also acts as a procoagulant. Secretion enhanced by hypoxia, stretch, cytokines, endotoxin. Effect of ET-1 depends on balance of receptors on each cell.

Question 14

Describe the mechanism of action of Angiotensin-II

Answer 14

Angiotensin II is a peptide hormone that acts via AT2R and AT1R receptors. AT2R -> vasodilation via prostacyclin. Also stimulates BrR to produce bradykinin which -> NO. Via AT1R it leads to vasocontriction due to increasing ET-1, increasing ROS (acting as a pro-inflammatory factor) which inhibits NO, increasing thromboxane. It also increase tissue factor which leads to coagulation. The levels of AT1R and AT2R determine the vascular effects of Angiotensin II.

Question 15

What is thromboxane?

Answer 15

A pro-coagulant and vasoconstrictor that is produced by platelets and it increases ROS which inhibits NO

Question 16

How does the permeability of endothelium relate to its barrier function?

Answer 16

Endothelium are permeable to molecules ranging from 0.5nm (Na) to 11.5nm (IgG) in diameter. This size selective sieving property is crucial for its roles in tissue fluid homeostasis, angiogenesis, vessel tone, host defence

Question 17

Explain the different pathways through which different sized molecules are transported in endothelial cells

Answer 17

Macro (>3nm) molecules, like albumin and IgG are transported through the transcellular pathway (transcytosis/vesicular transport).
Molecules <3nm (glucose, H2O, ions) pass through inter endothelial junctions through the paracellular pathway. These pathways work together to maintain tissue-oncotic pressure and maintain the endothelial barrier.

Question 18

What is the paracellular pathway permeability dependent on?

Answer 18

Tight/adherens junction integrity. The proteins in the junction associate with actin cytoskeleton which provides the junction with additional structural support. Also phosphorylation status of junctional proteins determines tethering force. Factors phosphorylating junctional proteins -> conformational change, weakening cell-cell binding. The conformational changes can also lead to the actin cytoskeleton reorganising into stress fibres which pull on junctions. Hypoxia and inflammatory mediators act in this way eg. thrombin, histamine, etc.

Question 19

What is the difference between vasculogenesis and angiogenesis?

Answer 19

Vasculo is the differentiation of precursor cells (angioblasts) into endothelial cells and the de novo formation of a vascular network. Angiogenesis is the growth of blood vessels from existing vasculature.

Question 20

Describe the process of angiogenesis

Answer 20

Multistep process, involving the breakdown of cell-cell adhesions, basement membrane degredation, cell migration, morphogenesis/coalescence of new vessels.

Question 21

Describe the process of angiogenesis

Answer 21

On stim by an angiogenic factor like VEGF, the endothelia become motile, extending filopodia to guide the development of a capillary sprout. Leading cell goes further out, trailing cells follow and divide to form a stalk. Pinocytic vesicles in the cell fuse together to form a lumen

Question 22

Name some regulators and triggers of angiogenesis

Answer 22

NO, VEGF, TGF-B, Fibroblast GF, PDGF, Integrins, junctional proteins, ECM componenents. Angiogenesis is often triggered by hypoxia and is important in wound healing

Question 23

Describe coagulation in normal healthy tissues

Answer 23

Normal, healthy endothelium has anti adhesive properties and produces anticoagulant factors to maintain blood fluidity. Damaged blood vessels (wound or inflammation) lead to activated endothelia which increase pro coagulant and decrease anti coagulant production.

Question 24

Describe different anti and pro coagulants and their mechanism of action.

Answer 24

Von Willebrand factor stimulates platelet aggregation, prostacyclin, NO, heparan sulphate proteoglycan inhibit it. Tissue factor stimulates blood coagulation, thrombomodulin and tf pathway inhibitor inhibit it. Plasminogen activator inhibitor 1 leads to fibrinolysis and tissue type plasminogen activator inhibits it. Platelets plug vessel walls along with a fibrin containing clot to allow repair. Fibrinolysis counteracts clotting

Question 25

Describe how the inflammatory response results in prevention of further damage to blood vessels

Answer 25

Inflammatory responses are complex biological responses to harmful stimuli such as pathogens and damaged cells. Blood vessels respond quickly via increased leukocyte extravasation, vasoconstriction, and thrombosis.

Question 26

Describe the mechanism of action of the inflammatory response in blood vessels

Answer 26

Endothelia coming into contact with pro-inflammatory agents like bacterial LPS, tumour necrosis factor-a, they express leukocyte binding receptors:
Selectins (E- and P-), Intracellular adhesion molecules 1 and 2, vascular endothelial adhesion molecule
These promote leukocyte adhesion, rolling, transmigration. P selectin encourages adhesion and platelet aggregation on endothelium surface. Endothelia also produce pro-inflammatory cytokines like CSF-1, monocyte chemotactic protein-1, ILs, chemokine RANTES. These all encourage adhesion and transmigration of leukocytes into underlying smooth muscle cells and extravascular tissue to help combat the disease

Question 27

How can cancer cells hijack vasculature in other ways?

Answer 27

Co-opting pre-existing vessels, vessel mimickry where tumour cells gain endothelial like properties and act as vessels, and cancer stem cells differentiating into endothelial cells

Question 28

How do natriuretic peptides act to reduce blood pressure?

Answer 28

They reduce blood volume and increase vasodilation by increasing urine production and also sodium excretion. Also increased glomerular filtration. ANP also increase vascular permeability.