Elevated repulsive guidance molecule-a mRNA in peripheral blood mononuclear cells are associated with impaired leptomeningeal collaterals in patients with middle cerebral artery occlusions

Abstract

Background: In the event of middle cerebral artery occlusion (MCAO), leptomeningeal collaterals (LMCs) play a crucial role in determining the survival of brain tissue distal to occlusion. Previous findings indicated that genes controlling arteriogenesis can impact the extent of LMCs. Therefore, probe for potential genetic parameters correlating of arteriogenesis may be clinically useful in predicting LMCs status in MCAO.During the screening process, we focused on repulsive guidance molecule a (RGMa), which has been reported to play a negative role in angiogenesis after stroke by decreasing the proliferation, migration, and tube formation of endothelial cells (ECs) in vivo and in vitro. Indeed, endothelial function plays a main role in arteriogenesis and is essential in determining the LMCs status. Therefore, in present study, we aimed to testify the hypothesis that RGMa might be associated with LMCs status in MCAO. Methods:We prospectively enrolled patients with acute M1 MCA +/− intracranial internal carotid artery (ICA) occlusions (n=96) and healthy controls (n=33). Status of LMCs was evaluated according to computed tomographic angiography (CTA) on admission. Baseline RGMa mRNA expression was quantified by using quantitative real-time PCR.Results: Patients with poor LMCs showed significantly higher RGMa mRNA levels than patients with good LMCs status (P=0.001) as well as healthy controls (P=0.002), respectively; whereas good LMCs group showed similar baseline RGMa levels than controls (P=1.000). RGMa mRNA level and baseline NIHSS score were independent predictors for impaired LMCs. Conclusions:In MCAO patients, elevated PBMCs RGMa mRNA levels were associated with impaired LMCs status, indicating that measurement of RGMa mRNA expression in the early phase of stroke, together with other clinical approaches, was logically expected to be useful for predicting LMCs status. Moreover, a role for RGMa in leptomeningeal arteriogenesis following ischemic stroke can be hypothesized.

Increase in repulsive guidance molecule-a (RGMa) in lacunar and cortical stroke patients is related to the severity of the insult

“…To our knowledge, there is only one previous publication in patients with acute stroke where the levels of RGMa mRNA were monitored in patients following acute stroke 7 . Similar to our study, the RGMa mRNA was extracted from Peripheral blood mononuclear cells (PBMCs) within hours of arrival to the hospital in patients with cortical stroke and middle cerebral artery occlusion 7 . In their study, patients with poor cerebral pial collaterals had a higher level of RGMa mRNA.…”

“…In their study, patients with poor cerebral pial collaterals had a higher level of RGMa mRNA. Poor pial collaterals is associated with severe stroke and a higher NIHSS 7,24 . This is similar to our results where patients with cortical stroke, especially with higher NIHSS were associated with significantly higher levels of RGMa mRNA.…”

“…In addition, blocking the increased expression of RGMa following ischemia/reperfusion in rodents has been shown to improve angiogenesis and neuronal recovery 6 . There is a recent report that an increase in RGMa was seen in acute stroke patients with MCA occlusion, and the expression was significantly higher in patients with poor collaterals 7 .…”

Repulsive Guidance Molecule-a and Central Nervous System Diseases

“…The mechanism may lie in RGMa inhibiting angiogenesis through VEGF, Ang2, Ang1, and BDNF ( Table 1 ) [ 34 , 35 ]. In addition, the increased RGMa in patients with MCAO may be related to leptomeningeal collateral damage, which can predict the pathological state of leptomeningeal collateral by measuring the expression of RGMa mRNA in the early stage of stroke ( Table 1 ) [ 53 ].…”

Comparability of Elezanumab Safety, Tolerability, and Pharmacokinetics in Healthy Japanese, Chinese, and White Participants

“…13 Repulsive guidance molecule A (RGMa) is a potent modulator of axonal growth, myelination, and downstream immunoregulatory molecules, which impact neuronal and oligodendroglial survival as well as regeneration after trauma or inflammation in the central nervous system and can also influence functional recovery. [14][15][16][17][18][19] Increased RGMa expression has been observed in patients following acute stroke 20,21 and SCI upregulates RGMa expression in the injured rodent, nonhuman primate, and human spinal cord. [22][23][24][25] Thus, neutralization of RGMa is a novel approach for treatment of various degenerative central nervous system diseases and conditions.…”