Blood Flow and Pressure 2024 (BS31019) PDF

Regulatory Physiology and Pharmacology BS31019 Regulation of Blood Flow and Blood Pressure Dr. Calum Forteath [email protected] dundee.ac.uk Page 1 Learning Objectives → By the end of this lec...

Regulatory Physiology and Pharmacology BS31019 Regulation of Blood Flow and Blood Pressure Dr. Calum Forteath [email protected] dundee.ac.uk Page 1 Learning Objectives → By the end of this lecture you should be able to: → Describe the structure of a blood vessel and identify the cellular components → Understand the mechanisms by which the body can regulate blood flow and pressure → Discuss the key signaling pathways involved in vascular function and explain how these go wrong in disease → Explain current pharmacological strategies to improve vascular reactivity and blood flow dundee.ac.uk Page 2 Contents 1. The structure of vasculature and how this regulates blood flow → ‘Layers’ of a blood vessel and their function → Modulation of vascular diameter 2. Hormonal Regulation of Vascular Tone → Vasodilators → Vasoconstrictors 3. The Metabolic Syndrome and Cardiovascular Disease → Diagnosis → Comorbidities 4. Atherosclerosis → Stages of atherosclerosis development 5. Current therapies for Metabolic Syndrome and Cardiovascular Diseases dundee.ac.uk Page 3 The Structure of the Vasculature- Blood Flow → Blood vessels carry blood around the body towards target organs and tissues → Systemic Arteries, arterioles and capillaries → Oxygenated blood and nutrients from left ventricle towards systemic organs → Systemic Veins, venules and capillaries → Deoxygenated blood and waste from periphery towards the right atria → Heart → Pulmonary blood vessels → Reoxygenation of blood at the lungs → Returned to heart for circulation dundee.ac.uk Page 4 The Structure of the Vasculature- Blood Pressure → ‘Blood pressure’ is the pressure exerted by the blood on the vessel wall → Tight regulation of blood pressure is essential for optimal delivery of oxygen and nutrients to target tissues → Vessel diameter regulates blood pressure and blood flow → Wider diameter = lower pressure exerted on vessel wall → Greater blood flow through wider vessel → Narrow diameter = higher pressure exerted on vessel wall → Less blood flow through narrow vessel dundee.ac.uk Page 5 The Structure of the Vasculature- Blood Pressure → Blood pressure differs between vessel types → Greatest pressure in larger systemic arteries → Pressure reduces with increasing number of vessels (e.g, fewer arteries than arterioles and capillaries) → Lowest pressure in larger systemic veins dundee.ac.uk Page 6 The Structure of Arteries and Arterioles → Arteries and arterioles → 3 main layers (tunics) → Intima → Endothelial cells + subendothelial space → Single-cell layer → First barrier to pathogens in the blood → Communicates with vascular smooth muscle to regulate diameter → Media → Vascular smooth muscles → Relaxation/constriction dictates vessel diameter → Adventitia/externa → Collagen rich (where sympathetic nerves embed) → External elastic lamina → Vaso vasorum (small blood vessels supplying the larger vessel in some larger vessels) → Vessel diameter regulates blood flow and pressure → Arteries and arterioles contain intimal, medial and external elastic layers dundee.ac.uk Page 7 The Structure of Veins and Venules → Veins and Venules → 3 main layers (tunics) → Intima → Endothelial cells → Media → Small amount of vascular smooth muscle → Externa → Usually thicker than in arteries/arterioles → Veins and venules have valves → Prevent backflow of blood → Veins and venules lack elastic layers dundee.ac.uk Page 8 The Structure of the Vasculature Role of the layers in vessel diameter → Arteries and arterioles specially designed to modulate diameter → Communication between endothelial cells and vascular smooth muscle cells → Relaxation/Contraction = Vasodilation/Vasoconstriction → Endothelial cells possess specific functions depending on tissue and organ → Fluid filtration → Hormone trafficking → Immune cell recruitment and signalling → Thrombolysis → Lipolysis → Vascular tone → And more! dundee.ac.uk Page 9 Hormonal Regulation of Vascular Tone → Hormones produced within and out with the vasculature can regulate vasomotor tone → 4 Key Players: → Nitric Oxide → Endothelial Derived Hyperpolarizing Factor (EDHF) NO EDHF → Endothelin-1 ET-1 → Angiotensin II (AngII) AngII dundee.ac.uk Page 10 The Vascular Endothelium-Vascular tone → Endothelial cells are capable of producing Nitric oxide → ‘Endothelium-Derived Relaxing Factor’ → Vasoactive hormone gas → Synthesized in the endothelium → Diffuses sub-endothelial space → Causes relaxation of vascular smooth muscle dundee.ac.uk Page 11 Hormonal Regulation of Vascular Tone- Nitric Oxide → Production of Nitric oxide → Stimulation of GPCR by ligand (e.g. ACh) → Multi-protein phosphorylation cascade → Intracellular calcium release → Calmodulin activation → eNOS activation → Conversion of L-Arginine to L-Citrulline with release of NO dundee.ac.uk Page 12 Hormonal Regulation of Vascular Tone- Nitric Oxide → Nitric oxide causes smooth muscle relaxation → NO activates Guanylyl cyclase → Converts GTP to cyclic GMP → Activates Protein Kinase G → Stimulates relaxation of muscle fibres dundee.ac.uk Page 13 Hormonal Regulators of Vascular Tone-Vasodilation → Endothelial Derived Hyperpolarizing Factor (EDHF) → Another endothelium-derived vasodilatory hormone → Believed to be substance or electrical signal → Hyperpolarizes smooth muscle by stimulated K+ efflux → Muscle relaxation → Important when NO production is compromised → Tends to influence organ blood flow more than systemic dundee.ac.uk Page 14 Hormonal Regulators of Vascular Tone-Vasoconstriction → The Endothelium also regulates vasoconstriction via production of Endothelin-1 (ET-1) → Acts on smooth muscle to induce vasoconstriction via smooth muscle intracellular calcium release Endopeptidase ECE dundee.ac.uk Page 15 Hormonal Regulators of Vascular Tone-Vasoconstriction → ET-1 also: → Inhibits eNOS → Reduces NO bioavailability → Promotes vascular inflammation dundee.ac.uk Page 16 Hormonal Regulators of Vascular Tone-Vasoconstriction → Angiotensin II → Produced in liver as Angiotensinogen → Multiple target tissues → Smooth muscle constriction via G- protein coupled receptor signalling and intracellular Ca2+ release → Excessive levels promotes high blood pressure and vascular inflammation dundee.ac.uk Page 17 Quick question! → I am a vasomodulatory hormone that’s produced in the endothelium but acts predominantly at the arteriole level within organs. What am I? ü Endothelial Derived Hyperpolarizing Factor (EDHF) dundee.ac.uk Page 18 The Metabolic Syndrome → The Metabolic Syndrome is defined as: “A constellation of interconnected physiological, biochemical, clinical, and metabolic factors that directly increases the risk of cardiovascular disease, type 2 diabetes mellitus, and all cause mortality” → Diagnostic criteria (WHO 1998): → Insulin resistance → Impaired glucose tolerance or impaired fasting glucose levels AND any 2 of the following: → Obesity ⇢ BMI > 30 kg/m2 (recent revision: Waist circumference >40in (M)/ 35in (F)) → Dyslipidaemia ⇢ Raised TGs (≥150 mg/dL) and/or reduced HDL (140:90mmHg) → Hypercholesterolaemia (LDL>150mg/dl, HDL6,1mmol/l) → Insulin resistance → Obesity (BMI>30kg/m2) → Smoking → Inactivity → Age → Hereditary dundee.ac.uk Page 25 Atherosclerosis → Atherosclerosis development can be broken down into 5 key stages: 1. Endothelial dysfunction 2. Immune cell infiltration 3. Fatty streak 4. Young plaque 5. Unstable plaque dundee.ac.uk Page 26 Atherosclerosis- Endothelial Dysfunction → Precedes onset of atherosclerosis → Can be measured as an indicator of atherosclerosis risk → Begins in response to cardiovascular risk factors and chronic inflammation → Loss of endothelium-derived vasomotor control → ↓NO production → ↑ET-1 → Characterised by → ↑ expression of adhesion molecules → ↑ chemokine and cytokine secretion → ↑ cell permeability → ↑ LDL oxidation dundee.ac.uk Page 27 Atherosclerosis- Immune cell infiltration → Infiltration of the sub-endothelial space by immune cells and ox-LDL → Characterised by: → Increased adhesion molecules present on endothelial cells → E-Selectin → P-Selectin → ICAM-1 → VCAM-1 → Initial recruitment of monocytes/macrophages → Followed by other immune cells → T and B cells → Neutrophils and dendritic cells dundee.ac.uk Page 28 Atherosclerosis- “Fatty Streak” → Further accumulation of ox-LDL and phagocytosis of ox-LDL by macrophages → Visible as a yellow ‘fatty streak’ on vessel lumen → Lipid droplets forming in vascular smooth muscle cytoplasm → Smooth muscle and fibroblast proliferation and migration → Phenotype change from the quiescent "contractile" phenotype state to the active "synthetic" state, leading to movement of cells from media to intima → Owing to dysregulated signalling of ET-1, NO and Ang- II dundee.ac.uk Page 29 Atherosclerosis- Young Plaque → Accumulation of ‘foam cells’ and thinning of ‘fibrous’ cap → Foam cells cluster creating hypoxic central core → Hypoxic core becomes necrotic → The now fibrous cap of the developing plaque begins to thin as the lesion grows → Plaque is stable but narrowing vessel lumen dundee.ac.uk Page 30 Atherosclerosis- Vulnerable Plaque → Plaque becomes unstable → Necrotic core → Calcification → Likely to rupture → Releasing thrombus → Occluding vessel dundee.ac.uk Page 31 The Role of Obesity in CVD → Weight gain is a major risk factor for MetS → 5% among the subjects of normal weight → 22% among the overweight → 60% among the obese → Weight increase of ≥2.25 kg over a period of 16 yr was associated with an up to 45% increased risk of developing the MetS → Major factor in the development of obesity is leptin resistance → Hyperleptinemia → Moderate weight loss (6.5% i.e. with diet) will improve all aspects of MetS → Also results in a ~25% reduction in leptin levels → 5% weight loss can help restore insulin sensitivity → Treating Obesity will help reduce MetS symptoms dundee.ac.uk Page 32 Adipocyte Dysfunction Promotes Atherosclerosis → Hyperinflammatory adipocytes release pro- inflammatory cytokines and adipokines → Contribute alongside → Insulin resistance → Leptin resistance → Increased FFA → Hypercholesterolaemia dundee.ac.uk Page 33 Dysregulation of Vasomodulatory Hormones in Metabolic Syndrome → ANGII → Increased levels and signalling → Promotes inflammation and smooth muscle proliferation, resulting in an atherogenic environment → ET-1 → Potent inflammatory peptide – promotes oxidative stress and immune cell recruitment in the vessel wall → Increased production and processing also supresses NO signalling promoting vasoconstriction → NO → Bioavailability of NO reduced via inhibition of eNOS and peroxinitrite production → EDHF → Decreased production and transport of EDHFs, impairing vascular responses dundee.ac.uk Page 34 Metabolic Syndrome and CVD: Summary → Pathophysiology of CVD and MetS is multifaceted → Wide array of therapies to treat numerous contributing factors: → Insulin Resistance → Inflammation → Oxidative stress → Cholesterol → Hyperglycaemia → Hypertension → Or target the vasculature dundee.ac.uk Page 35 Common Therapies for MetS and Atherosclerosis → Thiazolidinediones (TZDs/Glitazones), e.g pioglitazone → PPAR𝛾 agonsists → Insulin sensitizers → Increases HDL cholesterol → Anti-inflammatory effect in vessel wall → AMPK activators (Biguanides), e.g metformin → Complex I inhibition → Regulates glucose metabolism → Increases FA oxidation → Reduces inflammation → GLP1-RAs (e.g, dulaglitude, semaglutide) → Stimulates insulin secretion and suppresses appetite → Reduced blood glucose → Reduces blood pressure (due to diuretic effect), thereby reducing AngII production and vascular inflammation → SGLT inhibitors (dapagliflozin, empagliflozin) → Inhibits/slows glucose (re)absorption → Reduces blood glucose and volume → Reduces blood pressure → Improves endothelial and VSMC function dundee.ac.uk Page 36 Common Therapies for MetS and Atherosclerosis → HMG-CoA Reductase Inhibitors (Statins), e.g simvastatin → Cholesterol biosynthesis inhibitors → Increases HDL cholesterol levels → Decreases LDL cholesterol levels and oxidation → Dietary antioxidants e.g. vitamin C or E → Reduce ROS → Reduce LDL oxidation → Bariatric Surgery → Incudes weight loss/alleviates obesity burden → Weight loss associated with reduced peripheral and adipocyte inflammation, improved insulin and leptin sensitivity, and reduced circulating FFAs and TGs → Exercise/Physical Activity → Improved insulin sensitivity → Weight loss → Improved NO bioavailability dundee.ac.uk Page 37 Current Therapies for Vascular Dysfunction → Nitric oxide donors → Diazeniumdiolates and S-Nitrosothiols → Improves vasoresponsiveness → ACE inhibitors → E.g, captopril, benazepril → Reduces AngII production → Alleviates vasoconstriction/favours vasodilation → Reduces blood pressure → Endothelin receptor antagonists → E.g, Sitaxsentan and ambrisentan → Limited effectiveness → Endothelin Converting Enzyme (ECE) inhibitors → Currently untested in humans → Surgery dundee.ac.uk Page 38 Regulation of Blood Flow and Blood Pressure: Summary → The vasculature is specially structured to tightly regulate blood flow and pressure to appropriately supply target organs and tissue → Four key vasomodulatory hormones signal between layers of the vasculature to alter vessel diameter → The Metabolic Syndrome is a global health crisis which increases prevalence of cardiovascular diseases such as atherosclerosis → Atherosclerosis occurs over 5 key steps- initiated by endothelial dysfunction → Therapies which treat the metabolic syndrome reduce vascular damage and disease dundee.ac.uk Page 39 Questions!? → What was the most interesting thing you learned from this lecture and why? → Is there anything I can help you understand better? dundee.ac.uk Page 40 Questions!? → Please use discussion boards on the VLE → Email me at [email protected] Endothelial Function and Endothelium and atherosclerosis Dysfunction review dundee.ac.uk Page 41