In response to vascular injury, smooth muscle cells (SMCs) 2 exhibit a phenotypic change characterized by loss of contractility and abnormal proliferation, migration, and matrix secretion. This "synthetic" phenotype plays an active role in repair of the vascular damage. Upon resolution of the injury, local environmental signals within the vessel prompt SMCs to reacquire their "contractile" phenotype. SMC phenotype modulation contributes to the pathogenesis of numerous cardiovascular disorders, including PAH, post-angioplasty restenosis and atherosclerosis (1). Idiopathic PAH is a rare disease typically fatal because of right ventricular failure. PAH is characterized by elevated pulmonary vascular resistance and pulmonary arterial pressure with increased muscularization of small arteries, thickening or fibrosis of the intima, and the presence of plexiform lesions (2, 3). Proliferation and dedifferentiation of SMCs appear to be the major events in the formation of lesions found in pulmonary arteries of patients with PAH (2, 3). Several lines of evidence implicate the BMP pathway in the etiology of PAH. First, heterozygous mutations in the gene encoding BMPRII, the type II subunit of the BMP receptor, were identified in patients with both familial and sporadic PAH (4, 5). Furthermore, the presence of BMPRII mutations in PAH patients curtails the available therapeutic options, as the patients affected are unlikely to demonstrate vasoreactivity and respond to longterm therapy with calcium channel blockers (6, 7). Second, loss of expression of either the type I (8) or the type II subunit (9, 10) of the BMP receptor has been observed in sporadic or secondary forms of PAH. Third, transgenic mice expressing a catalytically inactive BMPRII mutant in SMCs are predisposed to develop PAH in response to different stimuli (11,12). Fourth, experimental induction of PAH in rodents via hypoxia or monocrotaline injection correlates with a down-regulation of either the type I or the type II BMP receptor and with a general repression of BMP signaling (13-15). Despite these overwhelming correlations, the etiological mechanism of action of the BMP signaling pathway in PAH remains unclear.BMPs represent the largest group in the transforming growth factor ␤ (TGF␤) superfamily of growth factors (16 -18). During embryonic development, the BMP pathway plays multiple essential roles in the induction of ventral mesoderm, cardiac myogenesis, and vasculogenesis (19). Targeted inactivation of the BMP signal transducers Smad1 and Smad5 display a severe vascular phenotype (20). However, the effects of BMPs on adult VSMCs are not completely understood. It has been reported that BMPs inhibit proliferation and induce apoptosis in serumstarved pulmonary artery smooth muscle cells (PASMC) (10,21). It is also known that BMP7 stimulates the maintenance of the SMC phenotype in aortic SMCs, while BMP2 and BMP4 appear to have opposing effects on expression of SMC-specific genes in . These results suggest that the effects of BMP signaling on VSMCs are compl...

The protein products of the tuberous sclerosis complex (TSC) genes, TSC1 and TSC2, form a complex, which inhibits the small G-protein, Ras homolog enriched in brain (Rheb). The vast majority of research regarding these proteins has focused on mammalian Target of Rapamycin (mTOR), a target of Rheb. Here, we propose that there are clinically relevant functions and targets of TSC1, TSC2 and Rheb, which are independent of mTOR. We present evidence that such non-canonical functions of the TSC-Rheb signalling network exist, propose a standard of evidence for these non-canonical functions, and discuss their potential clinical and therapeutic implications for patients with TSC and lymphangioleiomyomatosis (LAM).

In response to vascular injury, differentiated vascular smooth muscle cells (vSMCs) undergo a unique process known as "phenotype modulation," transitioning from a quiescent, "contractile" phenotype to a proliferative, "synthetic" state. We have demonstrated previously that the signaling pathway of bone morphogenetic proteins, members of the transforming growth factor ␤ family, play a role in the induction and maintenance of a contractile phenotype in human primary pulmonary artery smooth muscle cells. In this study, we show that a four-and-ahalf LIM domain protein 2 (FHL2) inhibits transcriptional activation of vSMC-specific genes mediated by the bone morphogenetic protein signaling pathway through the CArG box-binding proteins, such as serum response factor and members of the myocardin (Myocd) family. Interestingly, FHL2 does not affect recruitment of serum response factor or Myocd, however, it inhibits recruitment of a component of the SWI/SNF chromatin remodeling complex, Brg1, and RNA polymerase II, which are essential for the transcriptional activation. This is a novel mechanism of regulation of SMC-specific contractile genes by FHL2. Finally, aortic rings from homozygous FHL2-null mice display abnormalities in both endothelial-dependent and -independent relaxation, suggesting that FHL2 is essential for the regulation of vasomotor tone.Unlike skeletal and cardiac muscle cells, vSMCs 2 never terminally differentiate, but are capable of transitioning to a synthetic phenotype characterized by decreased vSMC marker gene expression, increased matrix deposition, and responsiveness to signals that lead to increased migration and growth (1).This plasticity is crucial for the normal development of vessels, homeostasis of blood pressure, and repair of injury, but it also contributes to the development of various vascular pathologies. Therefore, it is critical to understand the signaling pathways that modulate the phenotype of vSMCs to develop agents that can regulate aberrant vSMC responses in diseased vessels.Recently we demonstrated that the BMP signaling pathway plays an important role in the phenotype modulation of PASMCs. Activation of the BMP pathway is required not only for maintenance of the contractile phenotype in PASMCs, but also for induction of vSMC marker gene expression in nonSMCs, such as mouse mesenchymal C3H10T 1 ⁄ 2 (10T1/2) cells (2-4). BMPs are the largest group in the TGF ␤ superfamily of growth factors and play a crucial role in various physiological processes (5-7). During embryonic development, the BMP pathway participates in the induction of ventral mesoderm, cardiac myogenesis, and vasculogenesis (8). Heterozygous mutations in the gene encoding BMPRII, the type II subunit of the BMP receptor, were identified in patients with both familial and sporadic idiopathic pulmonary arterial hypertension (IPAH) (9, 10). IPAH is characterized by elevated pulmonary vascular resistance and pulmonary arterial pressure with increased muscularization of small arteries, thickening or fibrosis of the intima, ...