Progression of Established Atherosclerotic Lesions Is Not Inhibited by Endothelial Knockout of Caveolin-1-Brief...

Eradicating endothelial caveolae by deleting the Cav1 (caveolin-1) gene reduces LDL (low-density lipoprotein) uptake in arteries and efficiently prevents early atherogenesis, but the role in established atherosclerosis is unknown. Here, to examine CAV1 as a potential therapeutic target, we deleted endothelial Cav1 in mice after lesion development and analyzed the effect on LDL uptake and lesion progression.

To allow timed endothelium-specific Cav1 deletion, we generated male and female mice with floxed Cav1 alleles and endothelium-specific inducible Cre recombinase. Atherosclerosis was induced by virus-mediated PCSK9 (proprotein convertase subtilisin/kexin type 9) gene transfer and a high-cholesterol diet. After 16 weeks of lesion development, endothelial Cav1 deletion was induced by a series of tamoxifen injections, repeated after 4 weeks, and the mice were followed for another 4 weeks. Mice were injected with fluorescently labeled LDL at 1 and 18 hours before euthanasia to study uptake and retention in lesions. Sections of the aortic root were analyzed for lesion size, composition, and LDL accumulation.

Efficient conditional knockout of endothelial Cav1 was confirmed by CAV1 immunostaining and by the loss of caveolae by electron microscopy. Loss of endothelial Cav1 for 8 weeks reduced LDL entry into lesions but did not significantly decrease LDL retention, lesion lipid accumulation, fibrous tissue, or lesion size. In males, a reduction in macrophages was seen.

Targeting CAV1 does not efficiently block LDL entry or reduce lesion progression in established atherosclerosis. These findings open several questions for further research, including alternative LDL entry mechanisms that could circumvent caveolar transport in established atherosclerosis.