Increased cardiac remodeling in cardiac-specific Flt-1 receptor knockout mice with pressure overload

Abstract

Vascular endothelial growth factor (VEGF) inhibition has previously been shown to have damaging effects on the heart. Because the role of Flt-1 (a phosphotyrosine kinase receptor for VEGF) in cardiac function and hypertrophy is unclear, we generated mice lacking Flt-1 only in their cardiomyocytes (Flt-1 KO). The hearts from 8- to 10-week-old mice were measured by using echocardiography and histology. No significant differences were seen in fraction shortening, cross-sectional area of cardiomyocytes, and interstitial collagen fraction between littermate controls and KO mice at baseline. To test the hypothesis that Flt-1 is involved in cardiac remodeling, we performed transverse aorta constriction (TAC) by ligating the transverse ascending aorta. Four weeks after TAC, echocardiography of the mice was performed, and the hearts were excised for pathological analysis and Western blotting. No difference in mortality was found between Flt-1 KO mice and controls; however, KO mice showed a greater cardiomyocyte cross-sectional area and interstitial collagen fraction than controls. Western blotting indicated that AKT was activated less in Flt-1 KO hearts after TAC compared with that in control hearts. Thus, Flt-1 deletion in cardiomyocytes increased hypertrophy, fibrosis, and regression of AKT phosphorylation. Our study suggests that Flt-1 plays a critical role in cardiac hypertrophy induced by pressure overload via the activation of AKT, which seems to be cardioprotective.

Knee fibrosis is associated with the development of osteoarthritis in a murine model of tibial compression

“…The expression of collagens and profibrotic regulators, including Sox9 and Sfrp2, was robustly increased in the 1-week loaded limbs relative to nonloaded controls. Conversely, the expression of molecules that prevent the development of fibrosis, including Ppargc1a, Vegfa, Flt1, or Nr4a1, [33][34][35][36] was decreased after loading in the 1-week group. The 2-week loaded samples also had increased expression of collagen and matrix remodeling genes accompanied by reduced expression of Sost, which has known roles in F I G U R E 2 Immunohistochemical evaluation of the stromal compartment in fibrous tissues following loading in C57BL/6J mice.…”

“…and P < .05 Mlf1 [33][34][35][36]. Therefore, this model may be used to evaluate how the modulation of specific targets in early timepoints impacts the progression and development of knee fibrosis.…”

Insulin and β Adrenergic Receptor Signaling: Crosstalk in Heart

“…Recent evidence shows that cardiac insulin signaling is hyperactive in a pathological hypertrophic model induced by pressure overload [55]. Genetic inhibition of the InsR-Akt1 signaling pathway substantially attenuates hypertrophy, adverse remodeling, and dysfunction following transverse aortic constriction [55, 59–62]. Thus, activation of InsR signaling in pressure overload model appears to promote detrimental pathological hypertrophy.…”

Comprehensive clinically oriented workflow for nucleotide level resolution and interpretation in prenatal diagnosis of de novo apparently balanced chromosomal translocations in their genomic landscape

“…Although this receptor has been implicated in development and homeostasis of many organs, it is not yet associated with a human disorder (Tjwa et al 2003). Flt1 knockout mice models show increased angiogenesis, left ventricle wall thickening and enlargement of the left ventricle cavity, only the last of which is consistent with the DGRC0013 phenotype (Fong et al 1995;Mei et al 2015). However, it is not unsurprising that a disruption of a single allele in FLT1 is not totally representative of the loss-of function phenotype in the knockout mouse.…”