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. Author manuscript; available in PMC: 2019 Aug 3.
Published in final edited form as: Circ Res. 2018 Aug 3;123(4):477–494. doi: 10.1161/CIRCRESAHA.118.313237

Table 2.

A summary of representative genetic approaches used for evaluating the roles of EC-secreted factors in metabolic homeostasis.

Secreted Factor Model System Signaling Effect and Metabolic Phenotype Ref.
NO Foxo1/3/4EC−/− mice Constitutive insulin signaling and NO production in ECs and increased tyrosine nitration of hepatic IR, eNOS inhibition (L-NAME) inhibits HFD-induced insulin resistance in Foxo1/3/4EC−/− mice. Tsuchiya et al. (2013)114
Ship2EC−/− mice Decreased NO bioavailability and increased insulin resistance in fat and muscle Watt et al. (2017)115
eNOS gene variants Metabolic syndrome, T2DM González-Sánchez et al. (2007)116, Monti et al.(2003)117, Rittig et al.(2008)118
eNOS−/− mice Hyperinsulinemia, hyperlipidemia, insulin resistance, Duplain et al.(2001)119
Cook et al.(2003, 2004)120, 121
e/nNOS−/− mice Insulin resistance
 Shankar et al.(2000)122
e/n/iNOS−/− mice Visceral obesity, hypertriglyceridemia, glucose intolerance Nakata et al.(2008)123
ECM proteins Vegfaepi−/− mice Few islet ECs, loss of intraislet basement membrane, less insulin secretion Nikolova et al.(2006)124
NOD mice Degradation of islet basement membrane at onset of insulitis and diabetes Irving-Rodgers et al.(2008)125
TSP-1 TSP-1−/− mice, islet transplant-ation from WT/TSP-1−/− mice Decreased insulin secretion and glucose tolerance, TSP-1 derived from ECs is important for insulin secretion Olerud et al.(2011)126
HGF CCl4-induced mouse liver injury model, injected with VEGF agonist (Flt/KDR selective) VEGF/Flt1 induces HGF and reduces liver damage LeCouter et al.(2003)127
PDGF-CC Vegfr2iEC−/− and Pdgf-c−/−mice, Adenoviral PDGF-C Impaired WAT-beige transition, adenoviral PDGF-C improves glucose tolerance in HFD-obese mice. Seki et al.(2016)128
EL EL−/− or EL transgenic mice HDL cholesterol level is negatively associated with EL expression level. Ishida et al. (2003)129, Ma et al.(2003)130
EL−/− mice Decreased FAO and ATP accumulation in heart, more severe systolic dysfunction and LV dilation Nakajima et al. (2013)131
EL gene variants Strong association with HDL level Ma et al.(2003)130, Edmondson et al. (2009)132, Singaraja et al. (2013)133

iEC, inducible EC; epi, epithelial; NOD, non-obese diabetic; FAO, fatty acid oxidation