Secondary Signalling Mechanisms in Angiotensin Ii‐stimulated Vascular Smooth Muscle Cells

Abstract

1. Activation of vascular smooth muscle by angiotensin II results in the generation of two second messengers, inositol trisphosphate (IP3) and diacylglycerol (DG). 2. IP3 is responsible for mobilizing calcium from endoplasmic reticulum. This signal is transient, most likely serving to initiate calcium events leading to contraction, and is attenuated by activation of protein kinase C. 3. DG stimulates protein kinase C and ultimately Na+/H+ exchange, leading to intracellular alkalinization. Accumulation of DG/activation of protein kinase C is sustained, and may be enhanced by concurrent intracellular alkalinization. The delay in induction of the sustained response appears to be related to cellular processing of the angiotensin II-receptor complex. 4. Angiotensin II-stimulated, phospholipase C-mediated IP3 formation is also modulated by a pertussis toxin-insensitive guanine nucleotide regulatory protein. 5. The GTP binding protein, movement of the receptor-ligand complex, and the signals generated by the two second messengers, IP3 and DG, interact in a complex manner to cause an integrated response of vascular smooth muscle cells to angiotensin II stimulation.

Calcium-dependent increase in tyrosine kinase activity stimulated by angiotensin II.

“…AngIl is known to rapidly increase intracellular Ca2+ and diacylglycerol concentrations in target cells (5,(25)(26)(27). We have shown that Ca2+ mobilization but not protein kinase C activation is necessary for elevation of tyrosine phosphorylation in response to AngIl (5).…”

Angiotensin II Activation of Insulin-Like Growth Factor 1 Receptor Transcription Is Mediated by a Tyrosine Kinase–Dependent Redox-Sensitive Mechanism

“…10, 11 The effects of Ang II are mediated on binding to its G protein-coupled 7-transmembrane domain receptor. 12 The signaling cascade initiated by Ang II binding includes activation of phospholipase C and D, 13,14 with resultant hydrolysis of membrane phospholipids, 15 increases in cytosolic calcium, 16 activation of the serine-threonine protein kinase C (PKC), tyrosine phosphorylation of multiple proteins, 17,18 activation of the mitogen-activated protein kinase (MAPK) cascade, 19 -21 and increases in proto-oncogene expression. [22][23][24] Ang II has also been shown to stimulate membrane oxidase systems, such as NADH/NADPH oxidase.…”

Simultaneous Measurements of Cytosolic Free Calcium Level and Prostaglandin Synthesis Reveal a Correlation between Them in Perfused Monolayer of Cultured Rat Vascular Smooth Muscle Cells: Effects of Bradykinin and Angiotensin II.

“…We have also reported that either BK or AngII stimulates phosphoinositide hydrolysis (caused by phospholipase (PL) C activation) to create inositol 1, 4, 5-trisphosphate (Ins(1, 4, 5) P3 ), a messenger of intracellular calcium mobilization (Berridge 1987), in VSM cells (Takeuchi et al 1989a(Takeuchi et al , 1991 and indicated that either BK or AngII-induced increase in [Ca2+] i is mediated by Ins(1, 4, 5)P3, a product of PLC. Angiotensin II is also known to stimulate phosphoinositide hydrolysis accompanied by an increase in [Ca2] +i (Smith et al 1984 ;Nabika et al 1985 ;Griendling et al 1988 ;Takeuchi et al 1991). Taken these observations together, it has been hypothesized that the increase in [Ca2] +i, which is triggered by Ins(1, 4, 5)P3i in turn, contributes to the calcium-dependent synthesis of PG.…”