Use of Adenosine to Facilitate Localization and Repair of Internal Carotid Artery Injury during Skull Base Surgery: A Case Report and Literature Review.

BACKGROUND: Internal carotid artery (ICA) injuries represent a rare, potentially fatal complication of endoscopic endonasal skull base surgery (EESBS). The use of adenosine to induce transient hypotension and facilitate management of high-flow, high-pressure arterial lesions has been well-documented in neuro-endovascular literature. A similar setting in which adenosine-induced hypotension may prove beneficial is during the management of major vascular injury encountered during EESBS. METHODS: A case of ICA injury and subsequent repair during EESBS is presented. RESULTS: A 74-year-old female underwent endoscopic transsphenoidal resection for a recurrent pituitary adenoma. During suprasellar resection, the right cavernous ICA was inadvertently injured resulting in brisk bleeding. Immediate vascular tamponade was applied, and a crushed muscle graft was obtained. Two intravenous doses of adenosine were administered in quick succession to produce transient hypotension and facilitate repair of the injury with the graft. Neurovascular imaging revealed a small pseudoaneurysm which remained stable throughout the postoperative course. The patient underwent definitive stent embolization of the pseudoaneurysm 1 month following discharge. CONCLUSION: Prompt repair of ICA injury during EESBS is crucial, but often limited by poor visualization. Adenosine-induced hypotension has demonstrated great efficacy as an adjuvant in neurovascular clipping of intracranial aneurysms and remains a valuable tool for the endoscopic skull-base surgeon as well. In cases with high risk for ICA injury, adenosine should be readily available.

Role of Intraoperative Neurophysiologic Monitoring in Internal Carotid Artery Injury During Endoscopic Endonasal Skull Base Surgery.

OBJECTIVE: In the present study, we investigated the role of intraoperative neuromonitoring (IONM) in internal carotid artery (ICA) injury during endoscopic endonasal skull base surgery (EESBS). METHODS: The study group included all 13 patients who had experienced an ICA injury during EESBS with IONM from 2004 to 2017. The medical records were reviewed for the perioperative data. The IONM reports were reviewed to evaluate the baseline somatosensory evoked potentials (SSEP), electroencephalography (EEG), and brainstem auditory evoked potentials (BAEP) and their significant changes related to ICA injury and/or the subsequent surgical/endovascular interventions. RESULTS: All 13 patients had undergone SSEP and 7 patients had BAEP monitoring during surgery. EEG was added during emergent angiography following the surgery for 5 patients. Two patients showed significant SSEP changes, and one showed significant SSEP and EEG changes, indicating cerebral hypoperfusion. Of these 3 patients, patient 1 had experienced irreversible SSEP loss with postoperative stroke. Patients 2 and 3 had SSEP and/or EEG changes that had recovered to baseline after interventions without postoperative deficits. Despite ICA injury, 10 patients showed no significant SSEP and/or EEG changes, and all 7 patients with BAEP monitoring showed no significant BAEP changes, indicating adequate cerebral and brainstem perfusion, respectively. The injured ICA was sacrificed in 4 patients, of whom 3 showed stable SSEP and 1 had experienced irreversible SSEP loss. IONM correlated with the postoperative neurologic examination findings in all cases, adequately predicting the neurologic outcomes after ICA injury. CONCLUSION: SSEP and EEG monitoring can accurately detect cerebral hypoperfusion and provide real-time feedback during surgery. SSEP and EEG changes predicted for neurologic outcomes and guide surgical decisions regarding the preservation or sacrifice of the ICA. Comprehensive multimodality monitoring according to the surgical risks can serve to detect and guide the management of ICA injury in EESBS.

Mutation of Arginine 264 on ERα (Estrogen Receptor Alpha) Selectively Abrogates the Rapid Signaling of Estradiol in the Endothelium Without Altering Fertility.

OBJECTIVE: ERα (estrogen receptor alpha) exerts nuclear genomic actions and also rapid membrane-initiated steroid signaling. The mutation of the cysteine 451 into alanine in vivo has recently revealed the key role of this ERα palmitoylation site on some vasculoprotective actions of 17ß-estradiol (E2) and fertility. Here, we studied the in vivo role of the arginine 260 of ERα which has also been described to be involved in its E2-induced rapid signaling with PI-3K (phosphoinositide 3-kinase) as well as G protein in cultured cell lines. Approach and Results: We generated a mouse model harboring a point mutation of the murine counterpart of this arginine into alanine (R264A-ERα). In contrast to the C451A-ERα, the R264A-ERα females are fertile with standard hormonal serum levels and normal control of hypothalamus-pituitary ovarian axis. Although R264A-ERα protein abundance was normal, the well-described membrane ERα-dependent actions of estradiol, such as the rapid dilation of mesenteric arteries and the acceleration of endothelial repair of carotid, were abrogated in R264A-ERα mice. In striking contrast, E2-regulated gene expression was highly preserved in the uterus and the aorta, revealing intact nuclear/genomic actions in response to E2. Consistently, 2 recognized nuclear ERα-dependent actions of E2, namely atheroma prevention and flow-mediated arterial remodeling were totally preserved. CONCLUSIONS: These data underline the exquisite role of arginine 264 of ERα for endothelial membrane-initiated steroid signaling effects of E2 but not for nuclear/genomic actions. This provides the first model of fertile mouse with no overt endocrine abnormalities with specific loss-of-function of rapid ERα signaling in vascular functions.

Endothelial Scaffolding Protein ENH (Enigma Homolog Protein) Promotes PHLPP2 (Pleckstrin Homology Domain and Leucine-Rich Repeat Protein Phosphatase 2)-Mediated Dephosphorylation of AKT1 and eNOS (Endothelial NO Synthase) Promoting Vascular Remodeling.

OBJECTIVE: A decrease in nitric oxide, leading to vascular smooth muscle cell proliferation, is a common pathological feature of vascular proliferative diseases. Nitric oxide synthesis by eNOS (endothelial nitric oxide synthase) is precisely regulated by protein kinases including AKT1. ENH (enigma homolog protein) is a scaffolding protein for multiple protein kinases, but whether it regulates eNOS activation and vascular remodeling remains unknown. Approach and Results: ENH was upregulated in injured mouse arteries and human atherosclerotic plaques and was associated with coronary artery disease. Neointima formation in carotid arteries, induced by ligation or wire injury, was greatly decreased in endothelium-specific ENH-knockout mice. Vascular ligation reduced AKT and eNOS phosphorylation and nitric oxide production in the endothelium of control but not ENH-knockout mice. ENH was found to interact with AKT1 and its phosphatase PHLPP2 (pleckstrin homology domain and leucine-rich repeat protein phosphatase 2). AKT and eNOS activation were prolonged in VEGF (vascular endothelial growth factor)-induced ENH- or PHLPP2-deficient endothelial cells. Inhibitors of either AKT or eNOS effectively restored ligation-induced neointima formation in ENH-knockout mice. Moreover, endothelium-specific PHLPP2-knockout mice displayed reduced ligation-induced neointima formation. Finally, PHLPP2 was increased in the endothelia of human atherosclerotic plaques and blood cells from patients with coronary artery disease. CONCLUSIONS: ENH forms a complex with AKT1 and its phosphatase PHLPP2 to negatively regulate AKT1 activation in the artery endothelium. AKT1 deactivation, a decrease in nitric oxide generation, and subsequent neointima formation induced by vascular injury are mediated by ENH and PHLPP2. ENH and PHLPP2 are thus new proatherosclerotic factors that could be therapeutically targeted.

Mesenchymal stem cell-derived exosomes ameliorate erection by reducing oxidative stress damage of corpus cavernosum in a rat model of artery injury.

Erectile dysfunction (ED) is a common ageing male's disease, and vascular ED accounts for the largest proportion of all types of ED. One of the mechanisms of vascular ED in the clinic is arterial insufficiency, which mainly caused by atherosclerosis, trauma and surgical. Moreover, oxidative stress damage after tissue ischemia usually aggravated the progress of ED. As a new way of acellular therapy, mesenchymal stem cell-derived exosomes (MSC-Exos) have great potential in ED treatment. In the current study, we have explored the mechanism of MSC-Exos therapy in a rat model of internal iliac artery injury-induced ED. Compared with intracavernous (IC) injection of phosphate-buffered saline after artery injury, of note, we observed that both mesenchymal stem cells (MSCs) and MSC-Exos through IC injection could improve the erectile function to varying degrees. More specifically, IC injection MSC-Exos could promote cavernous sinus endothelial formation, reduce the organization oxidative stress damage, and improve the nitric oxide synthase and smooth muscle content in the corpus cavernosum. With similar potency compared with the stem cell therapy and other unique advantages, IC injection of MSC- Exos could be an effective treatment to ameliorate erectile function in a rat model of arterial injury.

Intraluminal Delivery of Simvastatin Attenuates Intimal Hyperplasia After Arterial Injury.

INTRODUCTION: Oral statins reduce intimal hyperplasia (IH) after arterial injury by only ∼25%. Alternative drug delivery systems have gained attention as carriers for hydrophobic drugs. We studied the effects of simvastatin (free vs hyaluronic acid-tagged polysialic acid-polycaprolactone micelles) on vascular smooth muscle cell (VSMC) migration, VSMC proliferation and intimal hyperplasia. We hypothesized both free and micelle containing simvastatin would inhibit VSMC chemotaxis and proliferation, and local statin treatment would be more effective than oral in reducing IH in rats following carotid balloon injury. METHODS: VSMCs pretreated with free simvastatin (20 minutes or 20 hours) or simvastatin-loaded micelles underwent chemotaxis and proliferation to platelet-derived growth factor. Next, rats that underwent balloon injury of the common carotid artery received statin therapy-intraluminal simvastatin-loaded micelles prior to injury, periadventitial pluronic gel following injury, or combinations of gel, micelle, and oral simvastatin. After 14 days, morphometric analysis determined the -intimal to medial ratio. Findings were compared to controls receiving oral simvastatin or no statin therapy. Statistical analysis was by analysis of variance for the in vitro experiments and a factorial general linear model for the in vivo experiments. RESULTS: The simvastatin-loaded micelles and free simvastatin inhibited VSMC chemotaxis (54%-60%). IH was induced in all injured vessels. Simvastatin in pluronic gel or micelles reduced IH compared to untreated controls (0.208 ± 0.04 or 0.160 ± 0.03 vs 0.350 ± 0.03, respectively); however, neither gel nor simvastatin-loaded micelles were superior to oral statins (0.261 ± 0.03). Addition of oral statins or combining both local therapies did not provide additional benefit. Micelles were the single greatest contributing factor in IH attenuation. CONCLUSIONS: Intraluminally or topically delivered statins reduced IH. The efficacy of single-dose, locally delivered statin alone may lead to novel treatments to prevent IH. The different routes of administration may allow for treatment during endovascular procedures, without the need for systemic therapy.

Carotid Artery Entrapment by the Hyoid Bone-A Rare Cause of Recurrent Strokes in a Young Patient.

The search for etiology of stroke in a young patient may present a diagnostic challenge. In rare cases, chronic trauma to the carotid artery may be the cause of cerebral thromboembolic events. The hyoid bone lies in close proximity to the carotid artery bifurcation, and anatomic variants have been implicated in carotid compression, stenosis, dissection, and pseudoaneurysm. We report a case of recurrent strokes in a 32-year-old woman due to an elongated hyoid bone causing thrombus formation in her right internal carotid artery (ICA), resulting in recurrent embolic strokes confirmed on diffusion-weighted magnetic resonance imaging. Computed tomography angiography of the neck and head demonstrated the right hyoid bone was located between the ICA and external carotid artery (ECA), just above the carotid bifurcation, with residual nonocclusive thrombus in the right ICA. Carotid duplex ultrasonography confirmed that with the neck in neutral position, the hyoid was located between the ICA and ECA; however, with neck rotation, the hyoid slipped across the ICA and out of the bifurcation. There was no evidence of carotid stenosis. After an initial course of anticoagulation and antiplatelet therapy, resection of the greater cornu of the hyoid bone with release of the right ICA was performed. One year postoperatively, the patient had complete return of neurologic function and had no further neurologic events. Hyoid bone entrapment of the carotid artery is a rare etiology of thromboembolic stroke caused by repetitive local trauma. The diagnosis can be confirmed by carotid duplex with provocative maneuvers. Partial hyoid resection is a safe and effective treatment to relieve recurrent symptoms. Hyoid bone entrapment may be an important and under-recognized cause of stroke in young adults.

Influence of luminal stenosis in aneurysmal and non-aneurysmal blunt cerebrovascular injury.

BACKGROUND: Current blunt cerebrovascular injury (BCVI) grading grossly differentiates injury characteristics such as luminal stenosis (LS) and aneurysmal disease. The effect of increasing degree of LS beyond the current BCVI grading scale on stroke formation is unknown. STUDY DESIGN: BCVI over a 3-year period were retrospectively reviewed. To investigate influence of LS beyond the BCVI grading scale within aneurysmal and non-aneurysmal BCVI, grade 2 BCVI were subdivided into BCVI with ≥ 25% and ≤ 50% LS and BCVI with > 50% and ≤ 99% LS. Grade 3 BCVI were subdivided into BCVI with pseudoaneurysm (PSA) without LS and BCVI with PSA and LS. We hypothesized increased LS beyond the current BCVI grade distinctions would be associated with higher rates of stroke formation. RESULTS: 312 BCVI were included, of which 140 were carotid BCVI and 172 vertebral BCVI. Sixteen carotid BCVI underwent endovascular intervention (EI) and 19 suffered a stroke. In carotid BCVI stroke rates increased sequentially with BCVI grade except in grade 3. There was a stroke rate of 12% in grade 1 carotid BCVI, 18% in grade 2, 6% in grade 3, and 31% in grade 4. In subgroup analysis for grade 2 carotid BCVI, BCVI with > 50% and ≤ 99% LS had higher rates of stroke (22% vs. 15%, p = 0.44) than BCVI with ≥ 25% and ≤ 50% LS. In subgroup analysis of grade 3 carotid BCVI, BCVI with PSA and LS had higher rates of stroke (9% vs. 4%, p = 0.48) than BCVI with PSA without LS. Higher rates of EI in grade 2 carotid BCVI with > 50% and ≤ 99% LS (22% vs. 5%, p = 0.14) and grade 3 carotid BCVI with PSA and LS (35% vs. 4%, p = 0.01) were noted in subgroup analysis. CONCLUSION: Higher percentage LS beyond the currently used BCVI grading scale has a non-significantly increased rate of stroke in both aneurysmal and non-aneurysmal BCVI. Grade 3 BCVI with PSA and LS seems to be a high-risk subgroup. Use of EI confounds modern measurement of stroke risk in higher LS BCVI.

Intermedin reduces neointima formation by regulating vascular smooth muscle cell phenotype via cAMP/PKA pathway.

BACKGROUND AND AIMS: Vascular smooth muscle cell (VSMC) dedifferentiation contributes to neointima formation, which results in various vascular disorders. Intermedin (IMD), a cardiovascular paracrine/autocrine polypeptide, is involved in maintaining circulatory homeostasis. However, whether IMD protects against neointima formation remains largely unknown. The purpose of this study is to investigate the role of IMD in neointima formation and the possible mechanism. METHODS: IMD1-53 (100ng/kg/h) or saline water was used on rat carotid-artery balloon-injury model. The mouse left common carotid-artery ligation-injury model was established using IMD-transgenic and C57BL/6J mice. Immunohistochemistry and immunofluorescence staining was used to detect the protein expression in rat carotid arteries. Radioimmunoassay was used to determine the serum IMD level. The hematoxylin andeosin staining was used for carotid arteries morphological testing. In vitro, for rat primary cultured VSMC phenotype transition, proliferation and migration assays, platelet-derived growth factor-BB (PDGF-BB) reagent and IMD1-53 peptide were added to the culture media at the final concentration of 20 ng/mL and 10-7mol/L respectively. Quantification of VSMC proliferation involved MTT and BrdU assay and migration was detected by wound-healing assay. Western blot and realtime PCR were used to detect the protein and mRNA levels of tissues or cells. RESULTS: With the rat carotid-artery balloon-injury model, IMD was significantly downregulated in injured arteries and plasma. Exogenous IMD1-53 greatly inhibited neointima formation and prevented VSMC from switching to a synthetic phenotype. With the left common carotid-artery ligation-injury model, IMD-transgenic mice showed less neointima formation than C57BL/6J mice. PDGF-BB reduced IMD mRNA expression in rat primary cultured VSMCs but increased that of its receptors, calcitonin receptor-like receptor or receptor activity-modifying proteins. Furthermore, PDGF-BB promoted VSMC proliferation and migration and transformed VSMCs to the synthetic phenotype, which was reversed with IMD1-53 treatment. Mechanistically, IMD1-53 maintained the contractile VSMC phenotype via the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway. CONCLUSIONS: IMD attenuated neointima formation both in the rat model of carotid-artery balloon injury and mouse model of common carotid-artery ligation injury. IMD protection may be mediated by maintaining a VSMC contractile phenotype via the cAMP/PKA pathway.

Endothelinergic Contractile Hyperreactivity in Rat Contralateral Carotid to Balloon Injury: Integrated Role for ETB Receptors and Superoxide Anion.

Temporal consequences of neurocompensation to balloon injury on endothelinergic functionality in rat contralateral carotid were evaluated. Rats underwent balloon injury in left carotid and were treated with CP-96345 (NK1 antagonist). Concentration-response curves for endothelin-1 were obtained in contralateral (right) carotid at 2, 8, 16, 30, or 45 days after surgery in the absence or presence of BQ-123 (ETA antagonist), BQ-788 (ETB antagonist), or Tempol (superoxide-dismutase mimic). Endothelin-1-induced calcium mobilization was evaluated in functional assays carried out with BQ-123, BQ-788, or Tempol. Endothelin-1-induced NADPH oxidase-driven superoxide generation was measured by lucigenin chemiluminescence assays performed with BQ-123 or BQ-788. Endothelin-1-induced contraction was increased in contralateral carotid from the sixteenth day after surgery. This response was restored in CP-96345-treated rats. Endothelium removal or BQ-123 did not change endothelin-1-induced contraction in contralateral carotid. This response was restored by BQ-788 or Tempol. Contralateral carotid exhibited an increased endothelin-1-induced calcium mobilization, which was restored by BQ-788 or Tempol. Contralateral carotid exhibited an increased endothelin-1-induced lucigenin chemiluminescence, which was restored by BQ-788. We conclude that the NK1-mediated neurocompensatory response to balloon injury elicits a contractile hyperreactivity to endothelin-1 in rat contralateral carotid by enhancing the muscular ETB-mediated NADPH oxidase-driven generation of superoxide, which activates calcium channels.

Wedelolactone, a plant coumarin, prevents vascular smooth muscle cell proliferation and injury-induced neointimal hyperplasia through Akt and AMPK signaling.

Wedelolactone (WDL) is a natural compound derived from Chinese herbal medicine Eclipta prostrate L, and has been reported to exhibit various effects potentially beneficial for human health. However, the possible preventive effects of WDL toward vascular remodeling and mechanisms involved have not been investigated to date. In this study, we investigated the effects of WDL on proliferation induced by platelet-derived growth factor (PDGF) in primary rat aortic smooth muscle cells (VSMCs) and on neointimal hyperplasia resulted from balloon injury in rats. WDL exhibited strong inhibitory effects against PDGF-induced VSMC proliferation. Cell cycle analysis revealed that WDL induced G0/G1 arrest and prevented cell cycle from entering S phase. Immunoblot analysis suggested that the cell cycle arrest induced by WDL was through Akt suppression and adenosine 5'-monophosphate-activated protein kinase (AMPK) activation, with a subsequent cyclin-dependent kinase inhibitor p21 induction and cyclin D1 inhibition. We also observed that WDL notably reduced neointima-to-media area ratio of balloon-injured rat common carotid arteries (CCAs) in comparison with those untreated balloon-injured CCAs. The regulation of WDL on protein expressions of Akt, AMPK and cyclin D1 in vivo were also consistent with that in vitro. Taken together, our results suggest WDL exhibits potential preventive effects toward vascular remodeling and neointimal hyperplasia through the reduction of VSMC proliferation via inhibition of Akt and activation of AMPK.

Blunt Traumatic Extracranial Cerebrovascular Injury and Ischemic Stroke.

BACKGROUND: Ischemic stroke occurs in a significant subset of patients with blunt traumatic cerebrovascular injury (TCVI). The patients are victims of motor vehicle crashes, assaults or other high-energy collisions, and suffer ischemic stroke due to injury to the extracranial carotid or vertebral arteries. SUMMARY: An increasing number of patients with TCVI are being identified, largely because of the expanding use of computed tomography angiography for screening patients with blunt trauma. Patients with TCVI are particularly challenging to manage because they often suffer polytrauma, that is, numerous additional injuries including orthopedic, chest, abdominal, and head injuries. Presently, there is no consensus about optimal management. Key Messages: Most literature about TCVI and stroke has been published in trauma, general surgery, and neurosurgery journals; because of this, and because these patients are managed primarily by trauma surgeons, patients with stroke due to TCVI have been essentially hidden from view of neurologists. This review is intended to bring this clinical entity to the attention of clinicians and investigators with specific expertise in neurology and stroke.

Pyk2 inhibition promotes contractile differentiation in arterial smooth muscle.

Modulation from contractile to synthetic phenotype of vascular smooth muscle cells is a central process in disorders involving compromised integrity of the vascular wall. Phenotype modulation has been shown to include transition from voltage-dependent toward voltage-independent regulation of the intracellular calcium level, and inhibition of non-voltage dependent calcium influx contributes to maintenance of the contractile phenotype. One possible mediator of calcium-dependent signaling is the FAK-family non-receptor protein kinase Pyk2, which is activated by a number of stimuli in a calcium-dependent manner. We used the Pyk2 inhibitor PF-4594755 and Pyk2 siRNA to investigate the role of Pyk2 in phenotype modulation in rat carotid artery smooth muscle cells and in cultured intact arteries. Pyk2 inhibition promoted the expression of smooth muscle markers at the mRNA and protein levels under stimulation by FBS or PDGF-BB and counteracted phenotype shift in cultured intact carotid arteries and balloon injury ex vivo. During long-term (24-96 hr) treatment with PF-4594755, smooth muscle markers increased before cell proliferation was inhibited, correlating with decreased KLF4 expression and differing from effects of MEK inhibition. The Pyk2 inhibitor reduced Orai1 and preserved SERCA2a expression in carotid artery segments in organ culture, and eliminated the inhibitory effect of PDGF stimulation on L-type calcium channel and large-conductance calcium-activated potassium channel expression in carotid cells. Basal intracellular calcium level, calcium wave activity, and store-operated calcium influx were reduced after Pyk2 inhibition of growth-stimulated cells. Pyk2 inhibition may provide an interesting approach for preserving vascular smooth muscle differentiation under pathophysiological conditions.

[Roentgen endovascular treatment of common carotid artery dissection after eversion carotid endarterectomy]. / Rentgenendovaskulyarnoe lechenie dissektsii obshchei sonnoi arterii posle eversionnoi karotidnoi endarterektomii.

The article deals with the use of self-expanding stents for endovascular treatment in patients presenting with dissection of the common carotid artery, exemplified by two clinical case reports. In both cases, dissection of the common carotid artery developed after eversion carotid endarterectomy. Intimal detachment was eliminated in both cases by implanting self-expanding stents. These cases demonstrated possibilities of roentgen endovascular methods of treatment making it possible to successfully replace a repeat, technically difficult surgical intervention for iatrogenic dissection of the common carotid artery.

MicroRNA-15b/16 Attenuates Vascular Neointima Formation by Promoting the Contractile Phenotype of Vascular Smooth Muscle Through Targeting YAP.

OBJECTIVE: To investigate the functional role of the microRNA (miR)-15b/16 in vascular smooth muscle (SM) phenotypic modulation. APPROACH AND RESULTS: We found that miR-15b/16 is one of the most abundant mRs expressed in contractile vascular smooth muscle cells (VSMCs). However, when contractile VSMCs get converted to a synthetic phenotype, miR-15b/16 expression is significantly reduced. Knocking down endogenous miR-15b/16 in VSMCs attenuates SM-specific gene expression but promotes VSMC proliferation and migration. Conversely, overexpression of miR-15b/16 promotes SM contractile gene expression while attenuating VSMC migration and proliferation. Consistent with this, overexpression of miR-15b/16 in a rat carotid balloon injury model markedly attenuates injury-induced SM dedifferentiation and neointima formation. Mechanistically, we identified the potent oncoprotein yes-associated protein (YAP) as a downstream target of miR-15b/16 in VSMCs. Reporter assays validated that miR-15b/16 targets YAP's 3' untranslated region. Moreover, overexpression of miR-15b/16 significantly represses YAP expression, whereas conversely, depletion of endogenous miR-15b/16 results in upregulation of YAP expression. CONCLUSIONS: These results indicate that miR-15b/16 plays a critical role in SM phenotypic modulation at least partly through targeting YAP. Restoring expression of miR-15b/16 would be a potential therapeutic approach for treatment of proliferative vascular diseases.