Abstract-Cerebral, coronary, and peripheral artery diseases combined represent the most frequent cause of death in developed nations. The underlying progressive occlusion of large conductance arteries can partially be compensated for by transformation of preexisting collateral arterioles to small artery bypasses, a process referred to as arteriogenesis. Because biomechanical forces have been implicated in the initiation of arteriogenesis, we have investigated the mechanosensitive expression of a pivotal proarteriogenic molecule, monocyte chemoattractant protein (MCP)-1, which governs the recruitment of circulating monocytes to the wall of the remodeling collateral arterioles. Using a new ear artery ligation model and the classic hindlimb ischemia model in mice, we noted that MCP-1 expression is significantly increased in collateral arterioles undergoing arteriogenesis already 24 hours after its onset. By mimicking proarteriogenic perfusion conditions in small mouse arteries, we observed that MCP-1 expression is predominantly upregulated in the smooth muscle cells, which solely sense changes in circumferential wall tension or stretch. Subsequent analyses of cultured endothelial and smooth muscle cells confirmed that cyclic stretch but not shear stress upregulates MCP-1 expression in these cells. Blockade of the mechanosensitive transcription factor activator protein-1 by using a specific decoy oligodeoxynucleotide abolished this stretch-induced MCP-1 expression. Likewise, topical administration of the decoy oligodeoxynucleotide to the mouse ear abrogated arteriogenesis through downregulation of MCP-1 expression and monocyte recruitment. Collectively, these findings point toward a stretch-induced activator protein-1-mediated rise in MCP-1 expression in vascular smooth muscle cells as a critical determinant for the initiation of arteriogenesis. T he combination of atherosclerosis in cerebral, coronary, and peripheral arteries and its sequelae represent the single most important cause of death in the industrialized world. Thrombotic occlusion of these large conductance arteries often causes severe ischemia in the affected tissues. Based on the clinical relevance of the disease, significant efforts have been made to offset its consequences by stimulating the growth of new blood vessels into the ischemic area. 1 However, angiogenesis per se is not sufficient to fully restore blood supply to the affected tissues. 2,3 Spontaneous enlargement of collateral arterioles to small arteries bypassing the occluded main artery, an adaptive remodeling process referred to as arteriogenesis, on the other hand, seems to be much more efficient in compensating for the consequences of atherosclerosis. 4,5 Morphologically, collateral arteriolar enlargement is associated with a corkscrew-like appearance that is the consequence of a growth in length between 2 fixed points. 6 On the molecular level, arteriogenesis is characterized by the upregulation of adhesion molecules such as intercellular adhesion molecule (ICAM)-1 and chemokines like...

Repulsive guidance molecule A (RGMa) is a potent inhibitor of neuronal regeneration and a regulator of cell death, and it plays a role in multiple sclerosis (MS). In autopsy material from progressive MS patients, RGMa was found in active and chronic lesions, as well as in normal-appearing gray and white matter, and was expressed by cellular meningeal infiltrates. Levels of soluble RGMa in the cerebrospinal fluid were decreased in progressive MS patients successfully treated with intrathecal corticosteroid triamcinolone acetonide (TCA), showing functional improvements. In vitro, RGMa monoclonal antibodies (mAbs) reversed RGMa-mediated neurite outgrowth inhibition and chemorepulsion. In animal models of CNS damage and MS, RGMa antibody stimulated regeneration and remyelination of damaged nerve fibers, accelerated functional recovery, and protected the retinal nerve fiber layer as measured by clinically relevant optic coherence tomography. These data suggest that targeting RGMa is a promising strategy to improve functional recovery in MS patients.

In the modern world, cardiovascular disorders are the leading cause of mortality in developed countries, which in most cases undergo a long subclinical phase that can last decades before the first clinical symptoms appear. Aside from the well-known risk factors related to lifestyle and genetics, there is growing evidence that in a proportion of cases, the predisposition to cardiovascular disease lies in prenatal life. Moreover, numerous historical cohort studies and animal models have shown a clear association between low birth weight and increased cardiovascular mortality in adulthood, including increased risk of hypertension, diabetes, dyslipidemia and coagulation disorders in children and adults. Besides premature birth, low birth weight in the majority of the cases is caused by intrauterine growth restriction (IUGR), which affects up to 10% of all births. Several clinical and experimental studies showed that IUGR fetuses present signs of cardiac dysfunction in utero that persist postnatally and may condition higher cardiovascular risk later in life. The present review discusses the importance of the long-term cardiovascular follow-up of the patients who suffered early or late IUGR in utero, particularly with regard to the long-term epidemiological studies in adults, prospective studies in children and the possible mechanisms that trigger IUGR and cardiovascular programming. Considering the high prevalence of IUGR and the progressing availability of intervention strategies, it is of the highest clinical relevance to detect cardiovascular risks as early as possible, to introduce timely preventive interventions and to adapt the lifestyle, in order to improve the long-term cardiovascular health outcome of IUGR cases.

Fetal growth restriction (FGR) because of placental insufficiency affects 5% to 7% of pregnancies and represents one of the leading causes of perinatal morbidity and mortality.1 Numerous historical cohort studies 2 and animal models 3 have demonstrated that FGR has a strong association not only with metabolic but also with primary cardiovascular remodeling that lead to long-term adverse consequences in later life. The rapid cell proliferation and differentiation during fetal growth are sensitive to any of the even smallest changes damaging the environment that can lead to permanent alterations in structural and functional constitution, which may persist into the adult life. 2 The heart is a central organ in the prenatal adaptation to placental insufficiency and fetal hypoxia. Previous studies have demonstrated remodeled hearts (more globular) with signs of systolic and diastolic dysfunction and preserved ejection fraction. [4][5][6] FGR cases are associated with prenatal adverse cardiac remodeling 4,5 that persists postnatally, 6 and low birth weight was linked to increased cardiovascular mortality in adulthood.2 Chronic pressure/volume overload together with hypoxia in utero have been postulated as the potential underlying mechanistic pathway of prenatal cardiovascular remodeling in FGR. 5,6 Editorial see p 759 Clinical Perspective on p 787Although evaluation of cardiac function with echocardiography has traditionally been limited to volume-based assessment, recent developments in cardiac ultrasound allow the noninvasive measurement of cardiac deformation with direct assessment of myocardial muscle by assessing regional Background-Fetal growth restriction (FGR) is associated with global adverse cardiac remodeling in utero and increased cardiovascular mortality in adulthood. Prenatal myocardial deformation has not been evaluated in FGR to date. We aimed to evaluate prenatal cardiac remodeling comprehensively in FGR including myocardial deformation imaging. Methods and Results-Echocardiography was performed in 37 consecutive FGR (defined as birthweight <10th centile) and 37 normally grown fetuses. A comprehensive fetal echocardiography was performed including tissue Doppler and 2-dimensional-derived strain and strain rate. Postnatal blood pressure measurement at 6 months of age was also performed. FGR cases showed signs of more globular hearts with decreased longitudinal motion (left systolic annular peak velocity: controls mean 6 cm/s [SD myocardial strain and strain rate. [7][8][9] Strain is defined as change in length/thickness of a segment of myocardium relative to its resting length and is expressed as a percentage; strain rate is the velocity of this deformation.7-9 Myocardial deformation imaging has demonstrated a high sensitivity for detecting preclinical myocardial dysfunction in various pathological conditions characterized by myocardial dysfunction, despite preserved ejection fraction, such as asymptomatic carriers of hypertrophic cardiomyopathy, sarcomeric mutations, Fabry disease, or myocardial ste...