Pulmonary hypertension (PH) is a multifaceted vascular disease where development and severity are determined by both genetic and environmental factors. Over the past decade, there has been an acceleration of the discovery of molecular effectors that mediate PH pathogenesis, including large numbers of microRNA molecules that are expressed in pulmonary vascular cell types and exert system-wide regulatory functions in all aspects of vascular health and disease. Due to the inherent pleiotropy, overlap, and redundancy of these molecules, it has been challenging to define their integrated effects on overall disease manifestation. In this review, we summarize our current understanding of the roles of microRNAs in PH with an emphasis on potential methods to discern the hierarchical motifs governing their multifunctional and interconnected activities. Deciphering this higher order of regulatory structure will be crucial for overcoming the challenges of developing these molecules as biomarkers or therapeutic targets, in isolation or combination.
Vinny Negi, Stephen Y. Chan
Occurrence of transient ischemic attacks (TIA) and cerebral strokes is a recognized risk associated with cocaine abuse. Here, we use a rodent model along with optical imaging to study cocaine-induced TIA and the associated dynamic changes in cerebral blood flow velocity (CBFv) and cerebrovasculature. We show that chronic cocaine exposure in mice resulted in marked cortical hypoperfusion, in significant arterial and venous vasoconstriction, and in a sensitized vascular response to an acute cocaine injection. Starting after 10 days of exposure, an acute cocaine challenge to these mice resulted in a TIA, which presented as hemiparalysis and was associated with an abrupt exacerbation of CBFv. The severity of the TIA correlated with the decreases in cortical CBFv such that the greater the decreases in flow, the longer the TIA duration. The severity of TIA peaked around 17–22 days of cocaine exposure and decreased thereafter in parallel to a reorganization of CBFv from superficial to deep cortical layers, along with an increase in vessel density into these layers. Here, we document for the first time to our knowledge evidence of a TIA in an animal model of chronic cocaine exposure that was associated with profound decreases in CBFv, and we revealed that while the severity of the TIA initially increased with repeated exposures, it subsequently improved in parallel to an increase in the vessel density. This suggests that strategies to accelerate cerebrovascular recovery might be therapeutically beneficial in cocaine abusers.
Jiang You, Nora D. Volkow, Kicheon Park, Quijia Zhang, Kevin Clare, Congwu Du, Yingtian Pan
Maintenance of vascular integrity in the adult animal is needed for survival, and it is critically dependent on the endothelial lining, which controls barrier function, blood fluidity, and flow dynamics. However, nodal regulators that coordinate endothelial identity and function in the adult animal remain poorly characterized. Here, we show that endothelial KLF2 and KLF4 control a large segment of the endothelial transcriptome, thereby affecting virtually all key endothelial functions. Inducible endothelial-specific deletion of
Panjamaporn Sangwung, Guangjin Zhou, Lalitha Nayak, E. Ricky Chan, Sandeep Kumar, Dong-Won Kang, Rongli Zhang, Xudong Liao, Yuan Lu, Keiki Sugi, Hisashi Fujioka, Hong Shi, Stephanie D. Lapping, Chandra C. Ghosh, Sarah J. Higgins, Samir M. Parikh, Hanjoong Jo, Mukesh K. Jain
In the central nervous system, endothelial cells (ECs) and pericytes (PCs) of blood vessel walls cooperatively form a physical and chemical barrier to maintain neural homeostasis. However, in diabetic retinopathy (DR), the loss of PCs from vessel walls is assumed to cause breakdown of the blood-retina barrier (BRB) and subsequent vision-threatening vascular dysfunctions. Nonetheless, the lack of adequate DR animal models has precluded disease understanding and drug discovery. Here, by using an anti-PDGFRβ antibody, we show that transient inhibition of the PC recruitment to developing retinal vessels sustained EC-PC dissociations and BRB breakdown in adult mouse retinas, reproducing characteristic features of DR such as hyperpermeability, hypoperfusion, and neoangiogenesis. Notably, PC depletion directly induced inflammatory responses in ECs and perivascular infiltration of macrophages, whereby macrophage-derived VEGF and placental growth factor (PlGF) activated VEGFR1 in macrophages and VEGFR2 in ECs. Moreover, angiopoietin-2 (Angpt2) upregulation and Tie1 downregulation activated FOXO1 in PC-free ECs locally at the leaky aneurysms. This cycle of vessel damage was shut down by simultaneously blocking VEGF, PlGF, and Angpt2, thus restoring the BRB integrity. Together, our model provides new opportunities for identifying the sequential events triggered by PC deficiency, not only in DR, but also in various neurological disorders.
Shuntaro Ogura, Kaori Kurata, Yuki Hattori, Hiroshi Takase, Toshina Ishiguro-Oonuma, Yoonha Hwang, Soyeon Ahn, Inwon Park, Wataru Ikeda, Sentaro Kusuhara, Yoko Fukushima, Hiromi Nara, Hideto Sakai, Takashi Fujiwara, Jun Matsushita, Masatsugu Ema, Masanori Hirashima, Takashi Minami, Masabumi Shibuya, Nobuyuki Takakura, Pilhan Kim, Takaki Miyata, Yuichiro Ogura, Akiyoshi Uemura
Amphetamine (AMPH) or methamphetamine (METH) abuse can cause oxidative damage and is a risk factor for diseases including pulmonary arterial hypertension (PAH). Pulmonary artery endothelial cells (PAECs) from AMPH-associated-PAH patients show DNA damage as judged by γH2AX foci and DNA comet tails. We therefore hypothesized that AMPH induces DNA damage and vascular pathology by interfering with normal adaptation to an environmental perturbation causing oxidative stress. Consistent with this, we found that AMPH alone does not cause DNA damage in normoxic PAECs, but greatly amplifies DNA damage in hypoxic PAECs. The mechanism involves AMPH activation of protein phosphatase 2A, which potentiates inhibition of Akt. This increases sirtuin 1, causing deacetylation and degradation of HIF1α, thereby impairing its transcriptional activity, resulting in a reduction in pyruvate dehydrogenase kinase 1 and impaired cytochrome
Pin-I Chen, Aiqin Cao, Kazuya Miyagawa, Nancy F. Tojais, Jan K. Hennigs, Caiyun G. Li, Nathaly M. Sweeney, Audrey S. Inglis, Lingli Wang, Dan Li, Matthew Ye, Brian J. Feldman, Marlene Rabinovitch
Optical imaging methods have been developed to measure lymphatic function in skin; however, the lymphatic system of many organs is not accessible to this technology. Since lymphatic transport of macromolecules from any organ proceeds to the blood circulation, we aimed to develop a method that can measure lymphatic function by monitoring the fluorescence in a superficial vein of an interstitially injected tracer. We selected a 40-kDa PEGylated near-infrared dye conjugate, as it showed lymphatic system–specific uptake and extended circulation in blood. Lymphatic transport to blood from subcutaneous tissue required a transit time before signal enhancement was seen in blood followed by a steady rise in signal over time. Increased lymphatic transport was apparent in awake mice compared with those under continuous anesthesia. The methods were validated in K14-VEGFR-3-Fc and K14-VEGF-C transgenic mice with loss and gain of lymphatic function, respectively. Reduced lymphatic transport to blood was also found in aged mice. The technique was also able to measure lymphatic transport from the peritoneal cavity, a location not suitable for optical imaging. The method is a promising, simple approach for assessment of lymphatic function and for monitoring of therapeutic regimens in mouse models of disease and may have potential for clinical translation.
Steven T. Proulx, Qiaoli Ma, Diana Andina, Jean-Christophe Leroux, Michael Detmar
Life-sustaining responses to low oxygen, or hypoxia, depend on signal transduction by HIFs, but the underlying mechanisms by which cells sense hypoxia are not completely understood. Based on prior studies suggesting a link between the β-adrenergic receptor (β-AR) and hypoxia responses, we hypothesized that the β-AR mediates hypoxia sensing and is necessary for HIF-1α accumulation. Beta blocker treatment of mice suppressed hypoxia induction of renal HIF-1α accumulation, erythropoietin production, and erythropoiesis in vivo. Likewise, beta blocker treatment of primary human endothelial cells in vitro decreased hypoxia-mediated HIF-1α accumulation and binding to target genes and the downstream hypoxia-inducible gene expression. In mechanistic studies, cAMP-activated PKA and/or GPCR kinases (GRK), which both participate in β-AR signal transduction, were investigated. Direct activation of cAMP/PKA pathways did not induce HIF-1α accumulation, and inhibition of PKA did not blunt HIF-1α induction by hypoxia. In contrast, pharmacological inhibition of GRK, or expression of a GRK phosphorylation–deficient β-AR mutant in cells, blocked hypoxia-mediated HIF-1α accumulation. Mass spectrometry–based quantitative analyses revealed a hypoxia-mediated β-AR phosphorylation barcode that was different from the classical agonist phosphorylation barcode. These findings indicate that the β-AR is fundamental to the molecular and physiological responses to hypoxia.
Hoi I. Cheong, Kewal Asosingh, Olivia R. Stephens, Kimberly A. Queisser, Weiling Xu, Belinda Willard, Bo Hu, Josephine Kam Tai Dermawan, George R. Stark, Sathyamangla V. Naga Prasad, Serpil C. Erzurum
Regeneration of hepatic sinusoidal vasculature is essential for non-fibrotic liver regrowth and restoration of its metabolic capacity. However, little is known about how this specialized vascular niche is regenerated. Here we show that activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) by its natural ligand bound to HDL (HDL-S1P) induces liver regeneration and curtails fibrosis. In mice lacking HDL-S1P, liver regeneration after partial hepatectomy was impeded and associated with aberrant vascular remodeling, thrombosis and peri-sinusoidal fibrosis. Notably, this “maladaptive repair” phenotype was recapitulated in mice that lack S1P1 in the endothelium. Reciprocally, enhanced plasma levels of HDL-S1P or administration of SEW2871, a pharmacological agonist specific for S1P1 enhanced regeneration of metabolically functional vasculature and alleviated fibrosis in mouse chronic injury and cholestasis models. This study shows that natural and pharmacological ligands modulate endothelial S1P1 to stimulate liver regeneration and inhibit fibrosis, suggesting that activation of this pathway may be a novel therapeutic strategy for liver fibrosis.
Bi-Sen Ding, Catherine H. Liu, Yue Sun, Yutian Chen, Steven L. Swendeman, Bongnam Jung, Deebly Chavez, Zhongwei Cao, Christina Christoffersen, Lars Bo Nielsen, Susan R. Schwab, Shahin Rafii, Timothy Hla
Angiogenesis and co-optive vascular remodeling are prerequisites of solid tumor growth. Vascular heterogeneity, notably perivascular composition, may play a critical role in determining the rate of cancer progression. The contribution of vascular pericyte heterogeneity to cancer progression and therapy response is unknown. Here, we show that angiopoietin-2 (Ang2) orchestrates pericyte heterogeneity in breast cancer with an effect on metastatic disease and response to chemotherapy. Using multispectral imaging of human breast tumor specimens, we report that perivascular composition, as defined by the ratio of PDGFRβ– and desmin+ pericytes, provides information about the response to epirubicin but not paclitaxel. Using 17 distinct patient-derived breast cancer xenografts, we demonstrate a cancer cell–derived influence on stromal Ang2 production and a cancer cell–defined control over tumor vasculature and perivascular heterogeneity. The aggressive features of tumors and their distinct response to therapies may thus emerge by the cancer cell–defined engagement of distinct and heterogeneous angiogenic programs.
Jiha Kim, Pedro Correa de Sampaio, Donna Marie Lundy, Qian Peng, Kurt W. Evans, Hikaru Sugimoto, Mihai Gagea, Yvonne Kienast, Nayra Soares do Amaral, Rafael Malagoli Rocha, Hans Petter Eikesdal, Per Eystein Lønning, Funda Meric-Bernstam, Valerie S. LeBleu
Larry N. Agbor, Stella-Rita C. Ibeawuchi, Chunyan Hu, Jing Wu, Deborah R. Davis, Henry L. Keen, Frederick W. Quelle, Curt D. Sigmund
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