Epidermal Growth Factor Receptor Inhibition Prevents Caveolin-1-dependent Calcifying Extracellular Vesicle Biogenesis

Abstract

BackgroundChronic kidney disease (CKD) increases the risk of cardiovascular disease, including vascular calcification, leading to higher mortality. Release of calcifying extracellular vesicles (EVs) by vascular smooth muscle cells (VSMCs) promotes the ectopic mineralization of vessel walls. Caveolin-1 (CAV1) protein plays a key role in formation of calcifying EVs in VSMCs. Epidermal growth factor receptor (EGFR) co-localizes with and influences the intracellular trafficking of CAV1.MethodsWe computationally analyzed 7651 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) and Framingham cohorts to assess potential correlations between coronary artery calcium and single nucleotide polymorphisms (SNPs) associated with elevated serum levels of EGFR. Using a diet-induced mouse model of CKD, we measured serum EGFR and assessed the potential of EGFR inhibition to prevent vascular calcification.ResultsIndividuals in the MESA and Framingham cohorts with SNPs associated with increased serum EGFR exhibit elevated coronary artery calcium. Mice with CKD developed widespread vascular calcification, which associated with increased serum levels of EGFR. In both the CKD mice and human VSMC culture, EGFR inhibition significantly reduced vascular calcification by mitigating the release of CAV1-positive calcifying EVs. EGFR inhibition also increased bone mineral density in CKD mice.ConclusionGiven that EGFR inhibitors exhibit clinical safety and efficacy in other pathologies, the current data suggest that EGFR may be an ideal target to prevent pathological vascular calcification.Subject termsGrowth Factors, Vascular Biology, Vascular Disease, Translational Study

The two facets of receptor tyrosine kinase in cardiovascular calcification—can tyrosine kinase inhibitors benefit cardiovascular system?

“…The evidence of EGFR involvement in the development of VC arises from the study of Nik et al (27), as illustrated in Figure 3. In a genetic association study, EGFR mutation has been strongly associated with the incidence of VC.…”

“…Another study assessed the relationship of CAC with CVD and cancer mortality and found a relationship between CAC with CVD and cancer mortality, which significantly differed for women and men (111). Additionally, a molecular study has shown an increase in CAV-1 in calcifying VSMC (27), which is similar to malignancy (112).…”

“…For instance, targeting EGFR using TKI (erlotinib) improves atherosclerosis in mice ( 17 ). Moreover, a selective TKI for EGFR (ErB1) has been demonstrated to alleviate VC ( 27 ). Additionally, crizotinib can ameliorate VC as well ( 99 ).…”