Targeted Deletion of PTEN in Smooth Muscle Cells Results in Vascular Remodeling and Recruitment of Progenitor Cells Through Induction of Stromal Cell–Derived Factor-1α

Abstract

Abstract-We previously showed that changes in vascular smooth muscle cell (SMC) PTEN/Akt signaling following vascular injury are associated with increased SMC proliferation and neointima formation. In this report, we used a genetic model to deplete PTEN specifically in SMCs by crossing PTEN LoxP/LoxP mice to mice expressing Cre recombinase under the control of the SM22␣ promoter. PTEN was downregulated with increases in phosphorylated Akt in major vessels, hearts, and lungs of mutant mice. SMC PTEN depletion promoted widespread medial SMC hyperplasia, vascular remodeling, and histopathology consistent with pulmonary hypertension. Increased vascular deposition of the chemokine stromal cell-derived factor (SDF)-1␣ and medial and intimal cells coexpressing SM-␣-actin and CXCR4, the SDF-1␣ receptor, was detected in SMC PTEN-depleted mice. PTEN deficiency in cultured aortic SMCs induced autocrine growth through increased production of SDF-1␣. Blocking SDF-1␣ attenuated autocrine growth and blocked growth of control SMCs induced by conditioned media from PTEN-deficient SMCs. In addition, SMC PTEN deficiency enhanced progenitor cell migration toward SMCs through increased SDF-1␣ production. SDF-1␣ production by other cell types is regulated by the transcription factor hypoxia-inducible factor (HIF)-1␣. We found SMC nuclear HIF-1␣ expression in PTEN-depleted mice and increased nuclear HIF-1␣ in PTEN-deficient SMCs. Key Words: smooth muscle cell Ⅲ PTEN Ⅲ neointima Ⅲ autocrine growth Ⅲ conditional knockout mouse S mooth muscle cell (SMC) accumulation in the arterial intima is a key event in the pathogenesis of atherosclerosis, postangioplasty/in-stent restenosis, and graft arteriosclerosis, 1 with changes in the biological function and phenotype of SMCs contributing to the pathology. 2 These conditions are characterized, to varying degrees, by dedifferentiation, migration, and proliferation of medial-derived SMCs to form the neointima. Recent data suggest that bone marrow-derived, circulating, and/or resident progenitor/ proinflammatory cells are recruited to the injured vessel, differentiate down a SMC lineage, and proliferate, thereby contributing to neointimal lesion formation. [3][4][5][6] Compelling evidence supports the contribution of both processes to intimal hyperplasia, and major advances have identified numerous factors involved in this complex pathobiology. However, the underlying mechanism(s) initiating lesion formation are not clearly defined. Increased SMC production of chemokines, such as stromal cell-derived factor (SDF)-1␣ (CXCL12), has been shown to be centrally involved in progenitor cell recruitment, 7 although their role in inducing an autocrine growth pathway within the artery wall itself is unknown. We focused on the hypothesis that SMCs are central mediators of the injury response. Perturbations in SMC signaling, result in the production of soluble factors that regulate significant SMC hyperplasia and progenitor/proinflammatory cell recruitment through an autocrine/paracrine mechanism.Under physio...

Rosiglitazone Attenuates Chronic Hypoxia–Induced Pulmonary Hypertension in a Mouse Model

“…Rosiglitazone failed to significantly increase PTEN expression in normoxic mice, suggesting that rosiglitazone-mediated attenuation of hypoxia-induced reductions in PTEN expression may be more complicated than simple stimulation of the PTEN promoter. The potential importance of reduced PTEN in pulmonary hypertension is further supported by evidence that genetic interruption of PTEN in vascular smooth muscle caused development of pulmonary hypertension and vascular remodeling in mice exposed to normoxia (22). These reports, along with the current study, suggest that CH stimulates PDGF signaling not only through enhanced PDGFRb expression in the lung, but also by inhibiting the expression of the regulatory phosphatase, PTEN.…”

“…In addition, PTEN is inhibited by ROS (18,19), and its expression can be stimulated by PPARg ligands (20,21). On the other hand, smooth muscle-targeted depletion of either PTEN (22) or PPARg (23) caused pulmonary hypertension in mice. Collectively, these findings prompted our examination of PPARg and its ability to regulate PDGF and PTEN signaling pathways in the lung during hypoxia.…”

XBP 1-Deficiency Abrogates Neointimal Lesion of Injured Vessels Via Cross Talk With the PDGF Signaling

“…52,53 Suppression of PI3K reduces neointima formation, 54 whereas suppression of phosphatase and tensin homolog increases SMC hyperplasia. 55 In this study, we found that XBP1 splicing contributed to neointima formation via regulating SMC migration and proliferation. High levels of XBP1 expression and splicing could be detected immediately post vascular injury, whereas XBP1 deficiency in SMC significantly reduced neointima formation.…”

Mesodermal Pten inactivation leads to alveolar capillary dysplasia-like phenotype

“…Deleris et al (11) found that PTEN is also expressed and active in VSMCs controlling the level of PIP3 and therefore potentially controlling VSMC proliferation. Another report (27) showed that absence of PTEN in VSMCs leads to vascular remodeling and increased progenitor cell recruitment. However, to date, the specific deletion of Pten in lung mesenchyme during development has not been reported.…”