Lecture 7 Physiology of the Vasculature I Flashcards Preview

CDL301 Cardiovascular Pharmacology > Lecture 7 Physiology of the Vasculature I > Flashcards

Flashcards in Lecture 7 Physiology of the Vasculature I Deck (44)
Loading flashcards...

What are the different types of blood vessels

Large arteries medium-sized arteries arterioles capillaries venules medium-sized veins and large veins


Outline the structure of the vascular wall

The innermost layer surrounds the lumen of the vessel and is called the tunica intima. This consists of a single cell layer of endothelial cells attached to the basement membrane. The next layer is the tunica media this layer contains the vascular smooth muscle as well as elastic tissue. The relative proportion of elastic tissue and vascular smooth muscle varies between different types of vessels. The outermost layer is the tunica adventitia or tunica externa. This consists of a protective layer made up of fibrous connective tissue and extracellular matrix proteins such as collagen


Below is a histological staining of a blood vessel label the endothelium vascular smooth muscle and fibrous connective tissue layers on the diagram

See completed labels


What are the two main ways that the endothelium and adjacent VSMCs communicate

Gap junctions and via the release of mediators from the endothelium that act on the vascular smooth muscle


What is the role of the glycocalyx

Under normal conditions where the endothelium lining the blood vessels is healthy there is a layer on top known as the glycocalyx. This consists of carbohydrate chains attached to the cell membranes of the endothelial cells. The glycocalyx as an anti-coagulant effect by preventing circulating cells from binding to the endothelial layer


What happens to the glycocalyx in disease and what is the effect of this

Activated/Dysfunctional endothelium in disease will shed the glycocalyx. This exposes cell adhesion molecules (CAMs) that allow immune system cells such as monocytes neutrophils and platelets to bind to the endothelium


Glycocalyx shedding is a phenomenon that only happens in disease T or F

F - Glycocalyx shedding is a normal response tissue injury infection and inflammation


Other than disease what other factors can cause glycocalyx shedding

Glycocalyx shedding can also occur at disturbed blood flow. This is where eddies and turbulent flow causes loss of glycocalyx


Outline the healthy endothelial cell signalling that goes on in the blood vessels

In healthy endothelium neurotransmitters such as acetylcholine histamine 5-HT and bradykinin bind to receptors and increase Ca2+. A rise in intracellular Ca2+ activates endothelial nitric oxide synthase (eNOS) which then converts arginine into NO and citrulline. NO diffuses out of the endothelium and acts on adjacent smooth muscle cells where it causes relaxation


High shear blood flow also increases Ca2+ and activates eNOS T or F



Outline what happens in activated endothelium during disease

Activated endothelium have shed their glycocalyx and then IL-1 thrombin and endotoxins activate the receptors of the endothelial cells leading to the production of endothelin 1 (ET-1). Meanwhile there is an increased upregulation of ROS ICAM-1 VCAM1 IL-8 and COX2. All these pathway act to cause vascular disease


Explain the role of Ca2+ and its downstream targets in the contraction of VSMCs

Activation of Ca2+ channels in the plasma membrane of the endothelium leads to an influx of Ca2+ ions. This rise in intracellular Ca2+ activates calmodulin. Calmodulin in the presence of Ca2+ activates MLCK which then phosphorylates inactive myosin allowing it to bind actin. Once phosphorylated and bound to actin myosin can mediate the contraction of the smooth muscle


What intrinsic mechanism in smooth muscle accounts for its relaxation

Myosin light chain phosphatase (MLCP) causes the relaxation of VSMCs by dephosphorylating myosin. This enzyme is constrictively active in the vasculature meaning that it will trigger relaxation as soon as the contractile stimuli has passed


What are the key differences between skeletal muscle and VSMCs

In contrast to skeletal muscle myosin in vascular smooth muscle needs to be phosphorylated in order to bind actin. The other key difference is that myosin light chain phosphatase (MLCP) is constitutively active in VSMCs and hence as Ca2+ levels fall there is a natural relaxation


How else can Ca2+ levels be raised inside vascular smooth muscle cells in order to trigger contraction

Receptors that activate IP3 can also lead to VSMC contraction via acting on IP3R and RyR1 receptors to cause store release of Ca2+


What are the two classes of contractile stimuli in the VSMCs

GPCRs that are GαQ coupled these activate PLC-γ and increase IP3 levels which feeds in to Ca2+. The other class are Ca2+ channels which act to directly increase intracellular Ca2+


Give some examples of contractile stimuli that raise IP3 levels

Endothelin A/B receptors the thromboxane prostanoid receptor (TP-R) the AT-1 (angiotensin II) receptor the histamine receptor as well as the αARs


Give some examples of contractile stimuli that directly raise Ca2+ levels

L-type voltage-gated Ca2+ channels ligand-gated cation channels such as P2X (ATP-activated) and TRP channels as well as store operated Ca2+ channels like Orai1


What are the three key players in VSMC relaxation and how do the broadly act

cGMP – produced from the activation of guanylate cyclase and causes a reduction in Ca2+ levels. cAMP – produced from the activation of adenylate cyclase and causes a reduction of Ca2+ levels. K+ channels – activation leads to K+ efflux and a hyperpolarisation of the membrane potential which in turn acts to decrease Ca2+ levels


What is the universal mechanism by which VSMC stimuli cause relaxation

All three mechanisms feed in to reduce Ca2+ levels which decreases the activity of MLCK activity. This means that MLCP activity now predominates due to its constitutive acitivity and can dephosphorylate myosin leading to its dissociation from actin and subsequent relaxation


What are the four classes of relaxile stimuli

NO from the endothelium GPCRs that are GαS coupled K+ channels and PDEs


Broadly how does NO cause vascular relaxation

NO from the endothelium activates guanylate cyclase which then increases the levels of cGMP. cGMP then activates PKG which phosphorylates and increases the activity of MLCP. Dephosphorylation of myosin by MLCP causes its dissociation from actin and thus relaxation of the VSMCs.


Broadly how do some GPCRs cause vascular relaxation

GPCRs that are coupled to GαS subunits stimulate adenylate cyclase and increase the activity of cAMP. cAMP then causes activation of PKA which also phosphorylates MLCP to increase its activity. In addition raised cAMP levels also cause a reduction in Ca2+ levels which decreases the activity of MLCK


Broadly how do some K+ channels cause vascular relaxation

K+ channel activation leads to K+ efflux and a hyperpolarisation of the membrane potential which in turn acts to decrease Ca2+ levels. This can occur through their direct activation through changes in the membrane potential or indirect activation through β-adrenoceptor agonist binding which activates the βγ subunit of the G-protein which can in turn activate GIRKs


Broadly how can regulation of PDEs cause vascular relaxation

PDEs hydrolyse cAMP and cGMP. Hence by inhibiting these enzymes you can reduce cAMP and cGMP hydrolysis this potentiating their activity and leading to relaxation


What are the 4 pathways by which the endothelium regulates the vascular smooth muscle and what is the effect of each pathway

NO release – relaxation prostanoid synthesis – relaxation or contraction endothelin release – contraction angiotensin II – contraction


What are the two effects of raising cAMP in vascular smooth muscle cells

Increased cAMP levels results in a decrease in Ca2+ levels which decreases the activity of MLCK. Meanwhile elevated cAMP also activates PKA. PKA phosphorylates MLCP and increases its activity. This switches the balance of these two proteins so that MLCP dominates and dephosphorylates myosin


NO is an important regulator of blood pressure and regional blood flow T or F



Where is eNOS usually found and what is the significance of this

eNOS is held within caveolae which acts to localise the enzyme to clusters of nearby receptors


NO is produce by NOS in the endothelium in response to what stimulus

Elevated Ca2+ levels in the endothelial cells