ID family protein expression and regulation in hypoxic pulmonary hypertension

Abstract

To address this, we evaluated pulmonary expression of ID proteins in a mouse model of hypoxia-induced PH. There is selective induction of ID1 and ID3 expression in hypoxic pulmonary vascular smooth muscle cells (VSMCs) in vivo, and ID1 and ID3 expression are increased by hypoxia in cultured pulmonary VSMCs in a BMPdependent fashion. ID4 protein is barely detectable in the mouse lung, and while ID2 is induced in hypoxic peripheral VSMCs in vivo, it is not increased by hypoxia or BMP signaling in cultured pulmonary VSMCs. In addition, the PH response to chronic hypoxia is indistinguishable between wild type and Id1 null mice. This is associated with a compensatory increase in ID3 but not ID2 expression in pulmonary VSMCs of Id1 null mice. These findings indicate that ID1 is dispensable for mounting a normal pulmonary vascular response to hypoxia, but suggest that ID3 may compensate for loss of ID1 expression in pulmonary VSMCs. Taken together, these findings indicate that ID1 and ID3 expression are regulated in a BMP-dependent fashion in hypoxic pulmonary VSMCs, and that ID1 and ID3 may play a cooperative role in regulating BMP-dependent VSMC responses to chronic hypoxia. hypoxia; bone morphogenetic protein signaling; ID1; ID2; ID3; vascular smooth muscle cells; endothelial cells GENETIC STUDIES IN PATIENTS with hereditary pulmonary arterial hypertension (HPAH) indicate that defective bone morphogenetic protein (BMP) type 2 receptor (BMPR2) signaling plays a critical role in promoting pulmonary hypertension (PH) and obliterative pulmonary vascular remodeling in this disease (16,25). Studies in mice carrying heterozygous null and hypomorphic germ line Bmpr2 mutations show that these mice do not develop spontaneous PH, but they have increased susceptibility to PH in response to inflammatory mediators and serotonin (22,38,39) or to chronic hypoxia (9). Conditional deletion of Bmpr2 in endothelial cells (ECs) promotes spontaneous PH in a subset of affected mice (11), indicating that defective BMPR2 signaling plays a role in regulating EC function. However, interference with BMPR2 signaling in vascular smooth muscle cells (VSMCs) by overexpression of a dominant negative BMPR2 mutation also promotes spontaneous PH in mice (45). Furthermore, conditional deletion of the BMP type 1 receptor ALK3 in VSMCs reduces hypoxic pulmonary vascular remodeling and VSMC proliferation (7). These findings indicate that defective BMPR2 signaling influences both the EC and VSMC compartments in the pulmonary vasculature. However, the relationship between defective BMP signaling and vascular cell phenotypes in HPAH is complex and poorly understood (23).One approach to explore this has been to investigate the downstream signaling pathways that mediate the effects of BMP receptor mutations in different pulmonary vascular cell types. These studies also enable us to interrogate PH-associated alterations in BMP signaling that occur in the pulmonary vasculature in the absence of BMPR2 mutations. Activation of the BMP receptors leads to COOH-termi...

Id proteins are critical downstream effectors of BMP signaling in human pulmonary arterial smooth muscle cells

“…These investigators reported that Id1 and 3 expression are increased by hypoxia in a BMP-dependent fashion in PASMCs. Id1 knockout mice did not develop more severe pulmonary hypertension during chronic hypoxic exposure than wild-type mice, which was thought to be due to the compensation by Id3 (14). Indeed, potential compensation of Id3 for Id1 is well recognized from studies in angiogenesis (30).…”

“…The potential role of Id1 and 3 has been explored previously in the chronically hypoxic mouse model of pulmonary hypertension (14). These investigators reported that Id1 and 3 expression are increased by hypoxia in a BMP-dependent fashion in PASMCs.…”

“…The Id3 antibody used in these studies is suitable for use in immunohistochemistry (14). We took advantage of this to examine the expression of Id3 in the lungs of mice harboring a heterozygous knockin of the human BMPR-II mutation, R899X, and wild-type littermates (3).…”

Molecular Mechanisms of Pulmonary Arterial Remodeling

“…In opposition to these findings, Id3 was elevated in response to hypoxia. The different Id3 expression suggests that this family of transcription factors may act cooperatively in regulating BMP-dependent SMC proliferation due to chronic hypoxia (95). While the molecular signaling events are still unclear, the cyclin-dependent kinase inhibitor proteins, p21 and p27, appear to be the targets for Id proteins (96).…”

The expression and roles of Id1 and Id2 in the aggressive phenotype of human oral squamous cell carcinoma cells

“…This study revealed that one of the poorly differentiated types of OSCC cells expressed Id1 but that most of the differentiated types slightly expressed Id1 or not at all, with the exception of HSC-2. In this study, we examined the effects of Id1 and Id2 but not that of Id3, since Id3 usually mirrors the expression pattern of Id1 [27]. Moreover, Id4 was not examined because it is strongly associated with brain tumors.…”