Chapter 14 Blood Pressure – Regulation and Pathology © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 14. 1 Physiological regulation of blood pressure FIGURE 14.1 Physiological regulation of blood pressure. Blood pressure control is based on Ohm’s law modified for fluid dynamics, where blood pressure is proportional to cardiac output and resistance to blood flow in peripheral vessels. Blood flow depends on cardiac output and blood volume, whereas resistance is determined mainly by the contractile state of small arteries. In general, cardiac output remains fairly stable, with increase in peripheral resistance being the major contributor to essential hypertension. Many physiological systems influence blood pressure including the sympathetic nervous system, hormones, vasoactive agents, and the renin–angiotensin system, amongst other complex interacting systems. RAS, renin–angiotensin system; ROS, reactive oxygen species; NO, nitric oxide. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 14.2 Mechanisms whereby different organ systems contribute to blood pressure elevation. While hypertension is a multiorgan disease, high blood pressure itself causes target organ damage, such as cardiac hypertrophy, vascular remodeling, renal dysfunction, and cerebral ischemia. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 14. 3 Mutations leading to changes in blood pressure FIGURE 14.3 Mutations leading to changes in blood pressure. Numerous mutations in the nephron, the filtering unit of the kidney, have been described that result in hypertension or hypotension. Pathways regulating NaCl reabsorption in the thick ascending limb of the loop of Henle, the distal convoluted tubule, and the cortical collecting tubule are shown. Mutations in these locations result in altered Na+, K+ and volume balance. MR, mineralocorticoid receptors; DOC, deoxycorticosterone. (Adapted from References 25,30). © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 14. 4 Vascular effects of Ang II and its receptors FIGURE 14.4 Vascular effects of Ang II and its receptors. Angiotensin II (Ang II) mediates effects through multiple G protein-coupled receptors (GPCR), including the AT1receptor (AT1R) and the AT2receptor (AT2R). The Ang II-derived peptide, Ang-(1-7), mediates effects via Mas receptor, also a GPCR. Most of the pathological actions of Ang II are induced through the AT1R. Effects mediated via AT2R and Mas receptor generally oppose those of AT1R. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 14. 5 The renin–angiotensin system (RAS) FIGURE 14.5 The renin–angiotensin system (RAS). The classical RAS involves renin production, which increases angiotensin I formation from angiotensinogen and ACE/chymase-induced angiotensin II formation from angiotensin I. New concepts related to the RAS include (1) pro-renin/ renin and its receptor; (2) Ang-(1-12) formation; (3) ACE II-induced formation of Ang-(1-7) and Ang-(1-9); Ang III formation and its interaction with AT1R; and (4) Ang IV formation. Angiotensinconverting enzyme, ACE; angiotensin-converting enzyme 2, ACE2; phosphoenolpyruvate, PEP; nNeutral endopeptidase, NEP; adenosine monophosphate, AMP; angiotensin II type 1 receptor, AT1R; angiotensin II type 2 receptor, AT2R. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 14.6 Activation of G-protein-coupled receptors (GPCR) by vasoactive agents regulates vasomotor tone through multiple mechanisms. Ligand binding to GPCR induces coupling to heterometric Gq proteins, to activate PLC, leading to generation of IP3 and DAG, resulting in increased [Ca2+]i that triggers phosphorylation of MLC20 and stimulation of contraction. GPCR activation also induces contraction through the RhoA/Rho kinase pathway that increases Ca2+ sensitivity by inhibiting MLCP. NADPH oxidase (Nox)-derived reactive oxygen species also influence Ca2+-sensitive pathways that stimulate contraction. PLC, phospholipase C; DAG, diacylglycerol; CAM, calmodulin; MLCP, myosin light-chain phosphatase; MLC, myosin light chain; MLCK, myosin light-chain kinase; O2–, superoxide; H2O2, hydrogen peroxide; p, phosphorylation; IP3, inositol trisphosphate; GPCR, G-protein-coupled receptor; Ang II, angiotensin II; ET-1, endothelin-1. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 14.7 Molecular events regulating vascular remodeling in hypertension. Increased activation of AT1R by Ang II leads to activation of multiple signaling pathways that stimulate cell growth, inflammation, fibrosis, and contraction. Signaling pathways include activation of mitogen-activated protein kinases (MAP), tyrosine kinases, RhoA/Rho kinase and phospholipase C (PLC)/Ca2+. Ang II is a potent stimulator of NADPH oxidase (Nox), a multisubunit enzyme, that when activated induces generation of reactive oxygen species (ROS), such as superoxide (O2–) and hydrogen peroxide (H2O2). ROS act as second messengers, which influence redox-sensitive signaling processes. Ang II also induces activation of receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR), through transactivation pathways that may involve the tyrosine kinase c-Src. These processes lead to vascular smooth muscle cell contraction, growth, inflammation, and fibrosis that contribute to arterial remodeling in hypertension. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 14. 8 Remodeling of vessels FIGURE 14.8 Remodeling of vessels. Changes in lumen diameter and media mass (cross-sectional area) define the different patterns of vascular remodeling.5,8,9 Vessel narrowing with increased wall thickness occurs in chronic hypertension (hypertrophic remodeling), while mild hypertension is associated with smaller lumen and no increase in cross-sectional area (eutrophic remodeling). (Adapted from References 103,107). © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease