Rationale The vascular adventitia is a complex layer of the vessel wall consisting of vasa vasorum microvessels, nerves, fibroblasts, immune cells, and resident progenitor cells. Adventitial progenitors express the stem cell markers, Sca1 and CD34 (AdvSca1 cells), have the potential to differentiate in vitro into multiple lineages, and potentially contribute to intimal lesions in vivo. Objective While emerging data support the existence of AdvSca1 cells, the goal of this study was to determine their origin, degree of multipotency and/or heterogeneity, and contribution to vessel remodeling. Methods and Results Using two in vivo fate-mapping approaches combined with a smooth muscle cell (SMC) epigenetic lineage mark, we report that a subpopulation of AdvSca1 cells is generated in situ from differentiated SMCs. Our data establish that the vascular adventitia contains phenotypically distinct subpopulations of progenitor cells expressing SMC, myeloid, and hematopoietic progenitor-like properties and that differentiated SMCs are a source to varying degrees of each subpopulation. SMC-derived AdvSca1 cells exhibit a multipotent phenotype capable of differentiating in vivo into mature SMCs, resident macrophages, and endothelial-like cells. Following vascular injury, SMC-derived AdvSca1 cells expand in number and are major contributors to adventitial remodeling. Induction of the transcription factor Klf4 in differentiated SMCs is essential for SMC reprogramming in vivo while in vitro approaches demonstrate that Klf4 is essential for maintenance of the AdvSca1 progenitor phenotype. Conclusions We propose that generation of resident vascular progenitor cells from differentiated SMCs is a normal physiological process that contributes to the vascular stem cell pool and plays important roles in arterial homeostasis and disease.

Objective PTEN inactivation selectively in smooth muscle cells (SMC) initiates multiple downstream events driving neointima formation, including SMC cytokine/chemokine production, in particular SDF-1α. We investigated the effects of SDF-1α on resident SMC and bone marrow-derived cells and in mediating neointima formation. Methods and Results Inducible, SMC-specific PTEN knockout mice (PTEN iKO) were bred to floxed-stop ROSA26-βGal mice to fate-map mature SMC in response to injury; mice received wild-type GFP-labeled bone marrow to track recruitment. Following wire-induced femoral artery injury, βGal(+) SMC accumulate in the intima and adventitia. Compared to wild-type, PTEN iKO mice exhibit massive neointima formation, increased replicating intimal and medial βGal(+)SMC, and enhanced vascular recruitment of bone marrow cells following injury. Inhibiting SDF-1α blocks these events and reverses enhanced neointima formation observed in PTEN iKO mice. Most recruited GFP(+) cells stain positive for macrophage markers, but not SMC markers. SMC-macrophage interactions result in a persistent SMC inflammatory phenotype that is dependent on SMC PTEN and SDF-1α expression. Conclusions Resident SMC play a multifaceted role in neointima formation by contributing the majority of neointimal cells, regulating recruitment of inflammatory cells, and contributing to adventitial remodeling. The SMC PTEN-SDF-1α axis is a critical regulator of these events.

Objective: This study was performed to assess the utility of selective small-molecule inhibitors of class I HDACs in a preclinical model of pulmonary hypertension. Methods and Results:Rats were exposed to hypobaric hypoxia for 3 weeks in the absence or presence of a benzamide HDAC inhibitor, MGCD0103, which selectively inhibits class I HDACs 1, 2, and 3. The compound reduced pulmonary arterial pressure more dramatically than tadalafil, a standard-of-care therapy for human pulmonary hypertension that functions as a vasodilator. MGCD0103 improved pulmonary artery acceleration time and reduced systolic notching of the pulmonary artery flow envelope, which suggests a positive impact of the HDAC inhibitor on pulmonary vascular remodeling and stiffening. Similar results were obtained with an independent class I HDAC-selective inhibitor, MS-275. Reduced pulmonary arterial pressure in MGCD0103-treated animals was associated with blunted pulmonary arterial wall thickening because of suppression of smooth muscle cell proliferation. Right ventricular function was maintained in MGCD0103-treated animals. Although the class I HDAC inhibitor only modestly reduced right ventricular hypertrophy, it had multiple beneficial effects on the right ventricle, which included suppression of pathological gene expression, inhibition of proapoptotic caspase activity, and repression of proinflammatory protein expression. Key Words: histone deacetylase Ⅲ pulmonary hypertension Ⅲ proliferation Ⅲ gene expression Ⅲ signaling pathways I n patients with pulmonary hypertension (PH), restricted blood flow through the pulmonary arterial circulation due to increased pulmonary vascular resistance often results in right-sided heart failure. Despite recent advances in the treatment of PH, the 5-year mortality rate for individuals with this disease still approaches 50%, which highlights an urgent need for novel therapeutics. 1 Current standards of care for patients with PH typically involve the use of vasoactive drugs, including endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins. More effective therapeutic strategies will likely be based on the combined use of vasodilators and agents that target distinct pathogenic mechanisms in PH, such as pulmonary vascular inflammation and fibrosis, as well as aberrant proliferation of smooth muscle cells, endothelial cells, and fibroblasts in the lung vasculature. 2 Additionally, because right ventricular (RV) failure is the cause of death in the majority of PH patients, 3,4 and it is unclear whether standards of care for left ventricular Original received October 8, 2011; revision received January 11, 2012; accepted January 18, 2012. In December 2011 HDACs control cell proliferation, inflammation, and fibrosis by catalyzing removal of acetyl groups from lysine residues in a variety of proteins. The 18 mammalian HDACs are encoded by distinct genes and are grouped into 4 classes. 6 Two broad-spectrum HDAC inhibitors are approved for the treatment of cancer. One of these compounds,...