The development of hypoxia-induced pulmonary hypertension (PH) is associated with lung inflammation and vessel infiltration by monocytes. Two major monocyte subsets showing differential expression of CCR2 and CX3CR1 receptors have been identified. Ly6C^hi monocytes are involved in inflammation and express high levels of CCR2 but low levels of CX3CR1 (Ly6C^hi CCR2^hi/CX3CR1^lo). Ly6C^lo monocytes are the noninflammatory subtype and express high levels of CX3CR1 (Ly6C^l°CCR2^lo/CX3CR1^hi).

To determine the roles for Ly6C^hi and Ly6C^lo monocytes in hypoxic PH in mice, we studied CX3CR1^-/-, CCL2^-/− or double CX3CR1/CCL2^-/− mice compared to wild type (WT) mice.

Development of hypoxia-induced PH was associated with a marked increase in lung mRNA levels of CX3CR1, CCR2 and of their respective ligands CX3CL1 and CCL2. FACs analysis revealed sustained increases in both monocyte subsets in blood but only a transient peak on day 3 of hypoxia exposure in lung tissue. Total lung macrophage counts remained unchanged. CX3CR1^-/− mice showed protection against hypoxic PH compared to WT mice, whereas CCL2^-/− mice and double CX3CR1/CCL2^-/− mice exhibited similar PH severity as did WT mice. Chronically hypoxic WT and mutant mice did not differ regarding lung Ly6C^lo monocytes, whereas Ly6C^hi counts were reduced in CCL2^-/− or double CX3CR1/CCL2^-/− mice compared to WT or CX3CR1^-/− mice. Total lung macrophage counts did not differ between WT and CCL2^-/− or double CX3CR1/CCL2^-/− mice but were markedly increased in CX3CR1^-/− mice. These results are consistent with previous studies showing that CCR2 deficiency exacerbates PH in hypoxic mice, and they support a prominent effect of the CX3CL1/CX3CR1 axis on pulmonary vascular remodeling. Accordingly, we found that CX3CL1 potentiated proliferation of cultured PA-SMCs from WT mice but not from CX3CR1^-/− mice.

CX3CR1 deficiency protects against hypoxia-induced PH by modulating monocyte recruitment and PA-SMC cell proliferation.