Class A Macrophage Scavenger Receptor Knockout Augments Vascular Hypertrophy In Angiotensin Ⅱ-induced Hypertension

It is well known that macrophages play an important role in cardiovascular disease. The macrophages are divided into two subtypes:the classic pro-inflammatory M1 and the alternative anti-inflammatory M2 macrophages. M1 related pro-inflammatory cytokines have been recognized as important players in hypertensive cardiovascular remodeling. Class A macrophage scavenger receptor (SR-A) is a multifunctional molecule that participates in macrophage-mediated inflammation. A high expression of SR-A in M2 macrophages indicates that SR-A may play a key role in regulation of M1/M2 macrophages polarization. We hypothesized that SR-A, a key modulator of inflammation, may steer macrophage polarization, which in turn influences vascular remodeling in response to angiotensin II (Ang II)-induced hypertension.In the present study, genetically identical littermates of SR-A-/- and SR-A+/+ mice were infused with Ang II through subcutaneous osmotic minipumps for 2 weeks. Chronic infusion of Ang II led to similar increase in systolic blood pressure in SR-A+/+ and SR-A-/- mice. Compared with SR-A+/+ hypertensive mice, SR-A-/-hypertensive mice displayed a marked augumentation of aorta remodeling, including vascular medial hypertrophy and vascular cell proliferation. Meanwhile, macrophage infiltration and M1/M2 polarization were measured by quantitative real time-PCR. Enhanced M1 macrophage polarization was observed in SR-A-/- mice, along with increased production of M1 signature cytokines including IL-6, TNF-a and iNOS.In vivo, as a result of more Ml proinflammatory cytokines produced by SR-A-/-peritoneal macrophages induced by Ang II, coculturing with SR-A-/- peritoneal macrophages promoted primary vascular smooth muscle cells proliferation, which can be inhibited by pentoxifylline, an inhibitor of TNF-a. Further studies demonstrated SR-A-/- macrophages magnified M1 classically activated pro-inflammatory genes response to lipopolysaccharide, while suppressed M2 markers expression response to IL-4 both in vitro and in vivo. And importantly, transplantation using bone marrow from SR-A-/- mice significantly augmented Ang II induced vascular remodeling in SR-A+/+ mice.We can concluded that SR-A attenuated hypertension-induced vascular remodeling by suppressing macrophage polarization toward a skewed M1 phenotype. Therefore, SR-A may exert a protective effect against hypertension-induced vascular remodeling, which may represent a new interventional target for treatment of hypertensive vascular disease and other target organ damage of hypertension.