Neutralization of CXCL12 attenuates established pulmonary hypertension in rats

Abstract

Aims The progressive accumulation of cells in pulmonary vascular walls is a key pathological feature of pulmonary arterial hypertension (PAH) that results in narrowing of the vessel lumen, but treatments targeting this mechanism are lacking. The C-X-C motif chemokine 12 (CXCL12) appears to be crucial in these processes. We investigated the activity of two CXCL12 neutraligands on experimental pulmonary hypertension (PH), using two complementary animal models. Methods and results Male Wistar rats were injected with monocrotaline (MCT) or were subjected to SU5416 followed by 3-week hypoxia to induce severe PH. After PH establishment, assessed by pulsed-wave Doppler echocardiography, MCT-injected or SU5416 plus chronic hypoxia (SuHx) rats were randomized to receive CXCL12 neutraligands chalcone 4 or LIT-927 (100 mg/kg/day), the C-X-C motif chemokine receptor 4 (CXCR4) antagonist AMD3100 (5 mg/kg/day), or vehicle, for 2 or 3 weeks, respectively. At the end of these treatment periods, echocardiographic and haemodynamic measurements were performed and tissue samples were collected for protein expression and histological analysis. Daily treatment of MCT-injected or SuHx rats with established PH with chalcone 4 or LIT-927 partially reversed established PH, reducing total pulmonary vascular resistance, and remodelling of pulmonary arterioles. Consistent with these observations, we found that neutralization of CXCL12 attenuates right ventricular hypertrophy, pulmonary vascular remodelling, and decreases pulmonary artery smooth muscle cell (PA-SMC) proliferation in lungs of MCT-injected rats and SuHx rats. Importantly, CXCL12 neutralization with either chalcone 4 or LIT-927 inhibited the migration of PA-SMCs and pericytes in vitro with a better efficacy than AMD3100. Finally, we found that CXCL12 neutralization decreases vascular pericyte coverage and macrophage infiltration in lungs of both MCT-injected and SuHx rats. Conclusion We report here a greater beneficial effect of CXCL12 neutralization vs. the conventional CXCR4 blockade with AMD3100 in the MCT and SuHx rat models of severe PH, supporting a role for CXCL12 in the progression of vascular complications in PH and opening to new therapeutic options.

The six-transmembrane protein Stamp2 ameliorates pulmonary vascular remodeling and pulmonary hypertension in mice

“…Secreted MCP-1, IL-6 and CXCL12 were shown to impact cellular responses in smooth muscle cells that are potentially relevant during vascular remodeling processes. MCP-1 [41,43] and CXCL12 [4,11,23] impact both smooth muscle cell proliferation and migration, whereas IL-6 appears to preferentially induce smooth muscle cell migration [30,40], findings that were confirmed in our analyses. Thus, these cytokines were the most promising candidates potentially explaining the observed inter-cellular cross-talk between macrophages and smooth muscle cells.…”

The protective effects of MSC‐EXO against pulmonary hypertension through regulating Wnt5a/BMP signalling pathway

“…Male rats were used to minimize hormonal effects (eg of oestrogen). [12][13][14] The animal protocols followed the guidelines of the Institutional Animal…”

Multiple roles of macrophage migration inhibitory factor in pulmonary hypertension

“…Engagement of MIF with CD74, CXC chemokine receptors (CXCR)-2, CXCR4 and CXCR7 is partly responsible for the multiple biological activities associated with MIF (1,24,49). Interestingly, several of these receptors exhibit a more intense immunoreactivity in lungs from patients with PAH and from rodents with established PH (5,10,16,18,23,40,45,52,65).…”