NADPH Oxidase 1 Mediates Acute Blood Pressure Response to Angiotensin II by Contributing to Calcium Influx in Vascular Smooth Muscle Cells

Abstract

Background: Reactive oxygen species (ROS) and calcium ions (Ca2+) are among the major effectors of Ang II (angiotensin II) in vascular smooth muscle cells. ROS are related to Ca2+ signaling or contraction induced by Ang II, but little is known about their detailed functions. Here, NOX (NADPH oxidase), a major ROS source responsive to Ang II, was investigated regarding its contribution to Ca2+ signaling. Methods: Vascular smooth muscle cells were primary cultured from rat aorta. Ca2+ and ROS were monitored mainly using fura-2 and HyPer family probes. Signals activating NOX were examined with relevant pharmacological inhibitors and genetic manipulation techniques. Results: Ang II–induced ROS generation was found to be biphasic: the first phase of ROS production, which was mainly mediated by NOX1, was small and transient, preceding a rise in Ca2+, and the second phase of ROS generation, mediated by NOX1 and NOX4, was slow but sizeable, continuing over tens of minutes. NOX1-derived superoxide in the first phase is required for Ca2+ influx through nonselective cation channels. AT1R (Ang II type 1 receptor)-G βγ -PI3K γ (phosphoinositide 3-kinase γ ) signaling pathway was responsible for the rapid activation of NOX1 in the first phase, while in the second phase, NOX1 was further activated by a separate AT1R-Gα q/11 -PLC (phospholipase C)-PKC β (protein kinase C β ) signaling axis. Consistent with these observations, aortas from NOX1-knockout mice exhibited reduced contractility in response to Ang II, and thus the acute pressor response to Ang II was also attenuated in NOX1-knockout mice. Conclusions: NOX1 mediates Ca2+ signal generation and thereby contributes to vascular contraction and blood pressure elevation by Ang II.

Vascular Inflammation and Smooth Muscle Contractility: The Role of Nox1-Derived Superoxide and LRRC8 Anion Channels

“…55 Vasoconstrictor agents that activate Nox1 to promote contraction and proliferation include serotonin, 45 endothelin, 56 and most prominently AngII. 44,57,58 There are two phases of O 2…”

“…Vasoconstrictor agents that activate Nox1 to promote contraction and proliferation include serotonin, 45 endothelin, 56 and most prominently AngII. 44,57,58 There are two phases of O 2 •− production by Nox1 in response to AngII. 58 The first is brief (seconds) and precedes and potentiates calcium influx through redox sensitive 59 transient receptor potential channel 3 nonselective cation channels.…”

“…44,57,58 There are two phases of O 2 •− production by Nox1 in response to AngII. 58 The first is brief (seconds) and precedes and potentiates calcium influx through redox sensitive 59 transient receptor potential channel 3 nonselective cation channels. The second phase follows the calcium transient, is more sustained (minutes), and coordinated with Nox4 and mitochondrial ROS production.…”

Unraveling the Underlying Molecular Mechanism of ‘Silent Hypoxia’ in COVID-19 Patients Suggests a Central Role for Angiotensin II Modulation of the AT1R-Hypoxia-Inducible Factor Signaling Pathway

“…Moreover, both ACE1 and Ang II play roles in the HIF-1α activation associated with pulmonary hypertension and vascular remodeling [ 111 , 112 , 113 ]. The Ang II/AT1R pathway was found to induce marked ACE1 upregulation and ACE2 downregulation in patients with hypertensive cardiopathy associated with the activation of the ERK1/2 and p38 MAP kinase [ 114 , 115 , 116 , 117 ]. It has been known for many years that HIF-1α is phosphorylated by p42 and p44 mitogen-activated protein kinases (MAPKs also known as ERK1/2), as opposed to by p38 MAPK inducing an upper shift migration of this protein at 12 kDa.…”

Mechanism of Hypoxia‐Mediated Smooth Muscle Cell Proliferation Leading to Vascular Remodeling

“…For example, ECs induce VSMC proliferation by secreting large amounts of endothelin-1 (ET-1), Ang II, PDGF-BB, and VEGF-A [ 18 , 19 ], which induce vasoconstriction and vascular hypertrophy [ 20 ]. In addition, VSMC proliferation and migration can be promoted by activating signaling pathways such as mitogen-activated protein kinase signaling (MAPK) [ 21 , 22 ], protein kinase A (PKA) [ 23 ], protein kinase C (PKC) [ 24 ], and phosphatidylinositol 3-kinase (PI3K) [ 25 ].…”