. 2021 Aug 2;12:701390. doi: 10.3389/fphar.2021.701390

TABLE 3.

A summary of selected studies implicating EGFR signaling in diabetes-induced vascular dysfunction.

Role of EGFR	Study model	Intervention	Results	Refs.
Endothelial EGFR compared to vascular smooth muscle (VSM) EGFR plays a minor role in obesity/DIVD	High-fat diet T2DM mice	Endothelial cell (EC) specific EGFR knockout	• A comparison of vascular function parameters in EC verus VSM-specific EGFR KO mice implied that EC-EGFR plays a minor role in mediating obesity/T2DM-induced vascular dysfunction	Schreier et al. (2021)
Vascular smooth muscle (VSM) specific deletion of EGFR prevents obesity and DIVD	High-fat diet T2DM mice	VSM-specific EGFR-knockout (KO)	• VSM-specific EGFR via ErbB2- ROCK–MRTF–SRF signalling mediates vascular dysfunctiom	Stern et al. (2020)
DIVD and vascular remodeling can be corrected by inhibition of EGFR by novel polymeric nanoparticles	STZ-induced T1DM wistar rats	PAMAM dendrimers	• AG1478 or PAMAMs (novel inhibitors of ErbBs) corrected abnormal vascular reactivity and vascular remodeling in diabetic MVB	Akhtar et al. (2019)
	STZ-induced T1DM wistar rats	AG1478		Akhtar et al. (2019)
Multiple downstream pathways are involved in EGFR- ErB2 mediated DIVD	STZ-induced T1DM wistar rats	Lapatinib	• lapatinib inhibits EGFR & ErbB2 activity in diabetic MVB and in VSMCs and reverses diabetes and hyperglycemia-induced changes in ERKs, ROCK, AKT, FOXO, eNOS, & NF-kB and prevents HG-induced apoptosis in VSMCs	Benter et al. (2015)
Src-dependent EGFR/ErbB2 transactivation via ang II leads to DIVD	STZ-induced T1DM wistar rats	Ang-(1–7)	• Ang-(1–7) inhibits diabetes-induced transactivation of ErbB receptors in isolated MVB and opposes downstream signaling changes in ERK1/2, p38 MAPK, ROCK, eNOS, and lkB-α	Akhtar et al. (2015)
Increased EGFR activity via NADPH-oxidase leads to DIVD	C57/BL6 and db⁻/db⁻ T2D mice	AG1478, or exogenous EGF, or gp-91 ds-tat	• T2DM or EGF alters vascular reactivity in MRA that could be corrected by AG1478. EGF increased ROCK expression in MRA that could be corrected by NOX inhibition	Kassan et al. (2015a)
EGFR-ErbB2 heterodimers via ERK1/2- ROCKs lead to DVID	STZ-T1DM wistar rats	AG825	• Chronic in vivo or acute ex vivo inhibition of ErbB2 or EGFR corrected DIVD in MVB and attenuated elevated ERK1/2 and ROCK signaling. First evidence for EGFR-ErbB2 heterodimerization presented in co-association/immunoprecipitation assays	Akhtar et al. (2013)
		Anti-ErbB2 siRNA
		AG1478
Elevated EGFR mRNA an early change in development of DIVD	STZ-T1DM wistar rats	AG1478	• Diabetes altered expression of over 1,300 genes in MVB. AG1478 treatment prevented 95% of these changes implying that EGFR is a key early change in the development of DIVD	Benter et al. (2009)
Elevated EGFR via reduced eNOS mediates DIVD	T2DM db/db mice	AG1478	• Altered vascular reactivity and reduced eNOS expression in MRA and CA of diabetic mice could be corrected by AG1478 treatment	Belmadani et al. (2008)
EGFR and ErbB2 mediate DIVD in carotid artery	STZ-T1DM wistar rats	AG1478	• Altered vascular reactivity in diabetic carotid artery could be corrected by AG1478 and AG825 implicating EGFR and ErbB receptors in mediating DIVD	Yousif et al. (2005)
EGFR and ErbB2 mediate DIVD in carotid artery	STZ-T1DM wistar rats	AG825		Yousif et al. (2005)
Increased EGFR signaling leads to DIVD in renal artery	STZ-T1DM wistar rats	AG1478	• Elevated EGFR and DIVD in renal artery could be corrected by AG1478 and genistein but not by diadzein	Benter et al. (2005b)
Increased EGFR signaling leads to DIVD in renal artery	STZ-T1DM wistar rats	Genistein diadzein		Benter et al. (2005b)
Elevated EGFR phosphorylation leads to DIVD in MVB	STZ-T1DM wistar rats	AG1478	• Diabetes-induced abnormal vascular reactivity in MVB was linked to increased EGFR phosphorylation that could be corrected by AG178 treatment	Benter et al. (2005a)
Elevated EGFR phosphorylation leads to DIVD in MVB	STZ-T1DM wistar rats	Genistein		Benter et al. (2005a)

STZ, streptozocin; MVB, mesenteric vascular bed; VSMC, vascular smooth muscle cell; HG, hyperglycemia; MRA, mesenteric resistance arteries, CA, coronary artery; DIVD, Diabetes induced vascular dysfunction; AG1478, A selective EGFR Inhibitor; AG825, A selective ErbB2 inhibitor; lapatanib, A dual EGFR and ErbB2 inhibitor; Genistein, A pan ErbB/tyrosine kinase inhibitor; Diadzein, an inactive analogue of genistein; Ang-(1–7), Angiotensin-(1–7); gp91 das-tat, specific inhibitor of NADPH oxidase (NOX); PAMAM, Polyamidoamine (as dendrimeric nanoparticles); ROCK, Rho kinase; MRTF, actin–myocardin-related transcription factor; SRF, serum response factor.