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Summary Cardiovascular Disease
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Summary lectures cardiovascular diseaseLecture 1: Introduction – Guido Krenning 13-04-2021
History of the cardiovascular system
Aristotle (384-322 BC) was the first to recognize different taxa in biology:
2 major life forms: simple (coldblooded, invertebrates) or complex (warm-blooded, vertebrates).
3 complexities: vegetative soul for nutrition, growth and reproduction (all life forms), sensitive soul
for sensation and mobility (animals and humans) and the rational soul for thought and reflection
(humans only)
Erasistratus (305-250 BC) made a functional description of the vascular system: transport of essential
substances (air, blood, movement) through the body via veins (blood), arteries (air, this was of course not
right) and nerves (unidentified substance, later electricity).
Galen (131-215) realized all vessels contain blood, arteries were more oxygenated and distribute it to
organs, veins were deoxygenated and came from the liver, also distribution. The theory of 4 body fluids
and temperaments; disbalances could lead to sickness and can be cured by blood-letting:
Phlegm (slime): relaxed, peaceful, quiet and easy-going;
Blood: talkative, enthusiastic, active and social;
Gele gal: independent, decisive, goal-oriented and ambitious;
Zwarte gal: introvert, analytical and detail-oriented.
William Harvey (1578-1657): first description of a closed cardiovascular system (systemic), including the
pulmonary system. Tying a vein empty heart, so veins transport to the heart. Tying an artery swelling
up of the heart, so arteries transport to the body. All veins, except for those in the neck, have valves that
maintain a one-directional flow.
Antonie van Leeuwenhoek (1632-1723): discovery of the microscope for cell biology studies.
Marcello Malpighi (1628-1694): using the microscope he saw that arteries and veins are connected via a
capillary network.
Wilhelm His Sr. (1831-1904): slicing of the heart and analyzing under the microscope showed that
capillaries were made of endothelial cells and originated during embryology.
Wilhelm His Jr. (1863-1934): discovered the bundle of His, where the heartbeat starts.
Henryk Hoyer (1891-1965): discovered the lymphatic system that drains interstitial fluid.
Florence Sabin (1871-1953): first woman in cardiology, blood and blood vessels originate from the
angioblast.
Eric Jaffe (1948): isolated endothelial cells in vitro (which sparked molecular research)
Micheal Gimbrone (1943) and Judah Folkman (1933-2008) discovered VEGF (vascular permeability factor)
and its overexpression in tumors to increase blood supply.
Endothelial cell function
Cardiovascular system contains heart, blood vessels and lymph vessels. It’s the largest organ and
challenged by a lot of diseases; all containing some form of endothelial dysfunction. New blood vessels
originate from different blood vessels in a process called angiogenesis.
From the heart back to the heart: highly muscularized arteries, arterioles, capillaries, venules and
big veins with valves and less muscle.
Every capillary network is different because of the different needs of an organ.
,The endothelium has cellular plasticity (heterogeneity of vasculature, organ specific EC phenotypes,
endothelial-mesenchymal transition) and functional plasticity (barrier function by adhesion molecules,
immunology by leukocyte migration, thrombogenicity, vasomotor function and vascularization). These
functions all are necessary for proper transport and metabolism (vascular permeability), thrombosis and
coagulation, inflammation and blood flow.
Endothelial barrier function
The endothelial barrier function is kept intact by tight junctions (occludins) that seal the endothelial layer
by fusion. Adherence junctions (VE-cadherin) are also important, these cause cell-cell connections. Gap
junctions lead to EC-EC communication by connection of the cytoplasm.
The EC barrier causes the formation of gradients in pressure and metabolites, and the inhibition of
leukocyte migration.
Regulation of thrombogenicity
Heparan-sulfaphates inhibit thrombosis (blood clot formation, often in a negative way). Coagulation factors
(PAI1, tPA, vWF) are secreted to occlude vessel damage. ECs also inhibit platelet aggregation by NO and
PGI2 secretion.
Endothelial regulation of the vasomotor response (lecture Buikema)
Endothelium produces vasoactive substances: vasodilation; NO, PGI2, EDHF and vasoconstriction;
endothelin-1 (ET1). So; relaxation is dependent on the endothelium. The EC knows when to provide
vasoconstrictors or vasodilators through blood flow: rubbing force (shear stress) lead to NO production
and ET1 inhibition (vasodilation), whereas damaging stimuli increase ET1 and inhibit NO (vasoconstriction).
NO is produced by eNOS, which converts arginine to citrulline, and oxygen to NO (anti-
inflammatory, anti-thrombogenic, vasodilator). During inflammation, substrate specificity is
changed to NAD(P), using oxygen to create oxygen radicals that stimulate ET1 production.
Inflammation is caused by endothelial cell damage: heat (leakage of plasma from blood vessels), redness
(leakage of blood cells from blood vessels), swelling (liquid accumulation), pain (nervous enervation by
extravasated plasma proteins). Accumulation of damage and loss of nutrient transport will lead to loss of
function. Endothelial dysfunction is important in cardiovascular diseases, but also the precursor of
diabetes, renal failure etc.
, Lecture 2: Development and function of the vascular system – Guido Krenning
13-04-2021
The vascular system is a huge organ, with the main function to transport oxygen, nutrients, hormones and
waste products. Blood goes from the left ventricle of the heart to the aorta, arteries, arterioles, capillaries,
venules, veins and vena cava, before entering the heart again in the right atrium.
Structure of blood vessels: 3 layers
Tunica externa (adventitia) is made of fibroblasts and collagens (ECM), is mainly there for stiffness
and the anchoring to the tissue;
Tunica media is made of smooth muscle cells and elastin fibers, regulating both vasoconstriction
and vasodilation;
Tunica intima is the inner wall of the blood vessel and is made of endothelial cells and the basal
membrane (only one cell layer). It functions in coagulation, transport and inflammation.
The layers are separated by elastic membranes: the lamina elastica interna between the tunica intima and
the tunica media, and the lamina elastica externa between the tunica media and the tunica externa.
From arteries to arterioles to capillaries to veins
- From large arteries to arterioles to capillaries: decrease in tunica externa and media. Capillaries only have
an endothelial layer (tunica intima). When the capillaries go to venules and veins, there is an increase in
tunica media and externa again.
Arteries are large blood vessels that transport blood away from the heart
Arterioles are small vessels that distribute the blood to the capillary bed
Capillaries are the smallest blood vessels that form a network in tissue to allow diffusion of
substances (O2, CO2, nutrients)
Venules are larger blood vessels that collect the blood from the capillary bed
Veins are large vessels that transport the blood from the venules back to the heart
So many different blood vessels are necessary to change the velocities: low velocity and higher gas
exchange in small blood vessels. Also the amount of vessels means big cross-sectional area.
Development of the vascular system
The development of the vascular system starts at day 12 post-fertilization. The extraembryonic vasculature
(placenta) develops from the blood islands, whereas the embryonic vasculature develops from the
mesoderm. A complete cardiovascular system is established 8 weeks post-fertilization.
- Different processes in the formation are vasculogenesis (primary capillary plexus formation from primitive
blood islands or angioblasts), differentiation, angiogenesis (new blood vessel sprouting from pre-existing
ones) and lymphangiogenesis (lymph vessel formation).
Blood vessel formation originates in the mesenchyme, regulated by a lot of factors
BMP4 mesenchyme differentiation
FGF-2 formation of blood islands and hemangioblasts
VEGF-A & angiopoietin vasculogenesis
VEGF-A, Notch & EphrinB2/EphB4 arterial-venous specification
VEGF-A, Notch & Wnt angiogenesis
VEGF-C lymph angiogenesis
TGFβ & PDGF recruitment of pericytes and SMCs
VEGF-A & angiopoietin angioadaptation/remodeling
Mesoderm and hemangioblasts formation
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