Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Figure 4 Renin angiotensin system-mediated pathophysiological changes in portal hypertension.  In the cirrhotic liver, the “classical axis” of the renin angiotensin system (RAS) predominates. The vasoconstrictor octapeptide angiotensin II (Ang II), via the Ang II type 1 receptor in hepatic stellate cells (HSC) increases the deposition of extracellular matrix proteins, creating a fixed barrier to portal blood flow within the cirrhotic liver. In addition, Ang II also increases intrahepatic vascular tone by stimulating contraction of activated HSCs and vascular smooth muscle cells (VSMCs). Reduced release of vasodilating intracellular signalling molecules such as nitric oxide (NO) from vascular endothelial cells (VECs) by the action of endothelial NO synthase further impairs intrahepatic vasodilatation. In contrast, the “alternate axis” of the RAS predominates in the cirrhotic splanchnic vascular bed. The vasodilator heptapeptide angiotensin-(1-7), via its Mas receptor and, the Mas related G protein coupled receptor type-D, increases the release of NO from VECs to promote the relaxation of VSMCs causing splanchnic vasodilatation. This condition may be exacerbated by intrinsic vascular hypocontractility of mesenteric arteries to vasoconstrictors such as Ang II. Other than NO activity, release of other potent endothelium-derived hyperpolarizing factors such as epoxyeicosatrienoic acids derived from arachidonic acid of membrane phospholipids may play an important role in splanchnic vasodilatation by increasing K⁺ efflux through Ca²⁺-activated K⁺ channels in VSMCs. These lead to an increased portal blood flow, resulting in increased portal pressure. ACE: Angiotensin converting enzyme; ACE2: Angiotensin converting enzyme 2; Ang II: Angiotensin II; AT1R: Angiotensin II type 1 receptor; Ang-(1-7): Angiotensin-(1-7); MasR: Mas receptor; MrgD: Mas-related G protein-coupled receptor-type D; HSC: Hepatic stellate cells; VSMCs: Vascular smooth muscle cells; VECs: Vascular endothelial cells; ECM: Extracellular matrix; eNOS/NO: Endothelial nitric oxide synthase/nitric oxide; EDHFs: Endothelium-derived hyperpolarizing factors; EETs: Epoxyeicosatrienoic acids; AA: Arachidonic acid; KCa²⁺: Ca²⁺-activated K⁺ channels.