Figure 10.

Pathophysiology of essential hypertension (HTN) in the MetS reloaded. This figure demonstrates the complex interconnected pathways between insulin resistance (IR encircled in red color) and HTN. IR is the cornerstone of the MetS reloaded, and this schematic depicts how it is related to the development of HTN (dashed red circle). Note the important role of endothelial derived nitric oxide (NO) (green), which is essential for proper vascular relaxation and homeostasis, and how it is negated (red-dashed diagonal line) in the development of HTN. Importantly, decreased bioavailable NO results in decreased vasorelaxation and increased vascular resistance with a resulting increase in vascular stiffening and elevated blood pressure (BP). Next, note the devastating role that reactive oxygen species (ROS) has on NO and endothelial cell dysfunction and activation, resulting in decreased vasorelaxation, increased vascular (Vasc) resistance, blood pressure elevation, vascular stiffness, and the role they each play in the development of HTN. Activation of the renin-angiotensin-aldosterone system (RAAS) is also very important to the development of HTN as well as the activation of the sympathetic nervous system (SNS). Importantly, note the involvement of the Leptin—Leptin resistance (LR) pathway in blue coloring. Furthermore, note the emerging roles of the endothelial glycocalyx (ecGCx), aberrant mitochondria (aMt), hyperhomocysteinemia (HHCY), and gut dysbiosis, which are related to inflammation via lipopolysaccharide (LPS), as these are emerging roles not only of the MetS reloaded but also in the development of HTN (colored in purple). The sum of these interacting pathways and functional changes are associated with vascular wall remodeling and vascular stiffening. This image adds additional information regarding some of the possible mechanisms in the development of HTN presented in figure nine because it focuses more on the involved possible mechanistic pathways in the development of HTN. Not shown is the relationship between the sodium/potassium ATPase enzyme that is redox-sensitive and the excessive redox stress in the MetS that is currently thought to also promote a salt-sensitive HTN due to the sodium/potassium ATPase enzyme inhibition. While some of these mechanisms may seem redundant, they are actually complementary to Figure 9. The inverse relationship between leptin and adiponectin also plays an important role, because when leptin is elevated, adiponectin is decreased, and thus there is a decrease in the A/L ratio that is associated with the loss of adiponectin’s protective vascular role. Importantly, systolic HTN predominates in the MetS reloaded. AGE/RAGE = advanced glycation end products and receptor for AGE; Akt = protein kinase B; ALDO = aldosterone; Ang II = angiotensin II; ECM = extracellular matrix; IGT = impaired glucose tolerance; IL-6 = interleukin-6; LPS = lipopolysaccharide; Na + = sodium; NF-κB = nuclear factor kappa B; PAMP = pathogen associated molecular pattern; PGN = proteoglycan; PI3K = phosphoinositide 3-kinase; PKC = protein kinase C; Sk = skeletal; T2DM = type 2 diabetes mellitus; TNFα = tumor necrosis factor-alpha; VSMC = vascular smooth muscle cell.