Milestone Papers on Signal Transduction Mechanisms of Hypertension and Its Complications

Abstract

To celebrate 100 years of American Heart Association-supported cardiovascular disease research, this review article highlights milestone papers that have significantly contributed to the current understanding of the signaling mechanisms driving hypertension and associated cardiovascular disorders. This article also includes a few of the future research directions arising from these critical findings. To accomplish this important mission, 4 principal investigators gathered their efforts to cover distinct yet intricately related areas of signaling mechanisms pertaining to the pathogenesis of hypertension. The renin-angiotensin system, canonical and novel contractile and vasodilatory pathways in the resistance vasculature, vascular smooth muscle regulation by membrane channels, and noncanonical regulation of blood pressure and vascular function will be described and discussed as major subjects.

Keywords: angiotensin II; endoplasmic reticulum stress; ion channels; microbiota; toll-like receptors.

Figure 1.. Signaling mechanism of the AT1 receptors in mediating vascular remodeling.

Upon AT1 receptor (AT₁R) activation, Gq coupled second messengers activate a metalloproteinase, ADAM17. This leads to production of an EGF receptor (EGFR) ligand, heparin-binding EGF like factor (HB-EGF) and activation of EGFR. EGFR activates ERK and other growth promoting cascades, thus it mediates vascular remodeling. This cascade appears independent from hypertension regulation by Ang II .

Figure 2.. Cell type specific roles of the AT1 receptors in mediating hypertension and associated pathology.

Cell type specific AT1A receptor (rodent major AT1 receptor) deletion studies helped us understand the cell type specific roles of the AT1 receptors. Vascular smooth muscle cells expressing AT1 receptor (SMC-AT₁R) are required for vascular remodeling including adventitial fibrosis in mice with chronic Ang II infusion. Ang II-dependent abdominal aortic aneurysm (AAA) development also requires SMC-AT₁R. While SMC-AT₁R is important for resistant artery constriction and elevation of blood pressure in response to Ang II infusion, sympathetic nerve stimulation by neuronal cells expressing AT₁R (NR-AT₁R) appears to elevate blood pressure and compensate for loss of SMC-AT₁R. Thus, hypertension still develops without SMC-AT₁R upon Ang II infusion. Cardiac or SMC AT₁R appears dispensable for cardiac hypertrophy in response to Ang II infusion. However, induction of hypertension is indispensable for Ang II-induced cardiac hypertrophy. In addition, proximal tubule AT₁R (PT-AT₁R) is essential for Ang II-induced hypertension by mediating enhancement of salt and water reabsorption .

Figure 3.

Signaling pathways underlying vascular smooth muscle cell contraction and relaxation. At the center of the signaling pathways is cytoplasmic calcium concentration, which increases upon influx from the extracellular space cation channels and release from internal (SR) stores following the stimulation of GPCRs by cognate agonists. K_IR – inward rectifying K⁺ channel; GPCR – G protein-coupled receptor; BK – Large-conductance Ca²⁺-activated K⁺ channel; TRP – transient receptor potential; VGCC – voltage-gated Ca²⁺ channel; ENaC – epithelial Na⁺ channel; sGC – soluble guanylyl cyclase; PLC – phospholipase C; PIP₂ – phosphatidylinositol 4,5-bisphosphate; DAG – diacyl glycerol; IP₃ – inositol 1,4,5-trisphosphate; Rho GEF – Rho guanine nucleotide exchange factor; PKC – protein kinase C; SR – sarcoplasmic reticulum; SERCA – sarcoendoplasmic reticulum Ca²⁺ ATPase; RyR – ryanodine receptor; PKG – protein kinase G; MLCK – myosin light chain kinase; MLCP – myosin light chain phosphatase; AC – adenylyl cyclase; Gα_x - α subunit of guanine nucleotide binding protein class; ACh – acetylcholine; E – epinephrine; NE – norepinephrine; ADO – adenosine; Ang II – angiotensin II; TXA₂ – thromboxane A₂; PGE₂ – prostaglandin E.

Figure 4.

Role of vascular smooth muscle ion channels in the pathogenesis of hypertension. Hypertension is characterized by (1) an increase in the expression of LTCCs, (2) an increase in PKCα-mediated persistent Ca²⁺ sparklets, (3) downregulation of Kv2.1 channels caused by Ca²⁺ sparklet-mediated activation of calcineurin and NFAT nuclear translocation, (4) an increased intermolecular coupling between TRPC3 channel and IP₃R1 in VSMCs enhancing TRPC3-mediated cation currents, (5) an increase in TRPC3 to TRPC6 subunit expression ratio, (6) an increase in angiotensin II-induced plasma membrane and mitochondrial TRPC3-medated Ca²⁺ influx, (7) a differential effect on TRPV4 microdomains manifesting as an increase in α1AR-PKCα-mediated TRPV4 currents and a decrease in TRPV4- activated BK currents, (8) an increased PKC activity inhibiting Rab11A-mediated trafficking of BKβ1 leading to BK channel dysfunction, and (9) deficiency of AT₂R-mediated BK_Ca channel activity. AT₁R: Angiotensin II type 1 receptor; AT₂R: Angiotensin II type 2 receptor; BK_Ca: Large-conductance Ca²⁺-activated K⁺ channels; LTCC: L-type Ca²⁺ channels; PKCα: Protein kinase Cα; CaM: Calmodulin; NFAT: Nuclear factor of activated T-cells; IP3R: Inositol triphosphate receptor; ER: Endoplasmic reticulum; ET-1: Endothelin-1; TRPC3: Transient receptor potential canonical 3; TRPC6: Transient receptor potential canonical 6; α1AR: α1 adrenergic receptor; TRPV4: Transient receptor potential vanilloid 4; BKα: α subunit of BK_Ca; BKβ1: β1 subunit of BK_Ca; ROS: Reactive oxygen species; ATP: Adenosine triphosphate.

Figure 5.. DAMPs, TLRs, Gut Dysbiosis and Hypertension:

Cell and/or tissue injury: e.g., increase in hydrostatic pressure (hypertension), trauma, apoptosis, or necrosis induce the release of mitochondria DAMPs including mitochondria DNA (mitDNA/CpGDNA) and mitochondria N-formyl peptides (NFPs). Mitochondria DAMPs are potent immunological instigators due to bacterial ancestry. Once DAMPs are released due to cell damage, they are recognized by pattern recognition receptors (PRRs) (e.g. Toll-like receptors (TLRs) and formyl peptide receptors (FPRs)) in VSMC and endothelial cells leading to an exacerbated generation of ROS and COX-1 and 2-derived prostaglandins and decreased NO bioavailability, and subsequent increased vascular contractility and reduced endothelial function. Further, the activation of FPR leads to vascular remodeling via increased actin polymerization. The figure also shows that hypertension presents with gut dysbiosis which is associated with increased gut permeability and bacterial fragments, such as LPS, bacterial NFPs, and CpGDNA, translocation to the circulation. These factors are recognized by TLR-4, FPR-1, and TLR-9 respectively in the vascular tissue.

Figure 6.. Mitochondria Dysfunction and Hypertension:

Overview of mitochondrial homeostasis in endothelial cell through fission and fusion (1). During perturbation (e.g., hypertension and inflammation) there is an increase in mitochondrial stress, and subsequently recruitment of the dynamin-1-like protein (Drp1) to the site of fission (2). Exacerbated activation of Drp1 leads to mitochondria superoxide production and inflammation in endothelial cells (3). Deletion of Drp1 and/or the use of inhibitors for the transcription factor, NFkB, decrease mitochondria fission and endothelial inflammation.