GPCR agonist-induced transactivation of the EGFR upregulates MLC II expression and promotes hypertension in insulin-resistant rats

Abstract

The presence of metabolic abnormalities such as insulin resistance and elevated levels of various vasoconstrictor G-protein-coupled receptor (GPCR) agonists contributes to the development of hypertension. Recent studies have suggested a link between disease progression and activation of growth factor receptor signalling pathways such as the epidermal growth factor receptor (EGFR) by matrix metalloproteinases (MMPs). We hypothesized that excessive stimulation of GPCRs such as alpha(1)-adrenergic receptors activates MMP-dependent EGFR transactivation and contributes to the development of hypertension by promoting increased synthesis of contractile proteins in vascular smooth muscle (VSM). We tested this concept in experiments using insulin-resistant VSM cells (VSMCs) and fructose hypertensive rats (FHRs), a model of acquired systolic hypertension and insulin resistance. We found that insulin resistance and agonist stimulation increased the expression and activity of MMPs (MMP-2 and MMP-7), the EGFR, contractile proteins such as myosin light chain kinase and MLC II, and their transcriptional activators including P90 ribosomal kinase (P90RSK) and serum response factor, possibly via the activation of extracellular signal-regulated kinase (ERK1/2) in VSMCs. Further, in insulin-resistant VSMCs and arteries from FHRs, disruption of MMP-EGFR signalling either by a pharmacological or small interfering RNA approach normalized the increased expression and activity of contractile proteins and their transcriptional activators and prevented the development of hypertension in FHRs. Our data suggest that the MMP-EGFR pathway could be a potential target in the treatment of hypertension in insulin resistance and/or hyperglycaemic conditions such as type 2 diabetes.