Arterial Hypertension Aggravates Innate Immune Responses after Experimental Stroke

Abstract

Arterial hypertension is not only the leading risk factor for stroke, but also attributes to impaired recovery and poor outcome. The latter could be explained by hypertensive vascular remodeling that aggravates perfusion deficits and blood–brain barrier disruption. However, besides vascular changes, one could hypothesize that activation of the immune system due to pre-existing hypertension may negatively influence post-stroke inflammation and thus stroke outcome. To test this hypothesis, male adult spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (WKYs) were subjected to photothrombotic stroke. One and 3 days after stroke, infarct volume and functional deficits were evaluated by magnetic resonance imaging and behavioral tests. Expression levels of adhesion molecules and chemokines along with the post-stroke inflammatory response were analyzed by flow cytometry, quantitative real-time PCR and immunohistochemistry in rat brains 4 days after stroke. Although comparable at day 1, lesion volumes were significantly larger in SHR at day 3. The infarct volume showed a strong correlation with the amount of CD45 highly positive leukocytes present in the ischemic hemispheres. Functional deficits were comparable between SHR and WKY. Brain endothelial expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and P-selectin (CD62P) was neither increased by hypertension nor by stroke. However, in SHR, brain infiltrating myeloid leukocytes showed significantly higher surface expression of ICAM-1 which may augment leukocyte transmigration by leukocyte–leukocyte interactions. The expression of chemokines that primarily attract monocytes and granulocytes was significantly increased by stroke and, furthermore, by hypertension. Accordingly, ischemic hemispheres of SHR contain considerably higher numbers of monocytes, macrophages and granulocytes. Exacerbated brain inflammation in SHR may finally be responsible for larger infarct volumes. These findings provide an immunological explanation for the epidemiological observation that existing hypertension negatively affects stroke outcome and mortality.

Microglia and Monocyte-Derived Macrophages in Stroke

“…These results suggest that chronic systemic hypertension deregulates microglial responses and support the importance of injury-induced activation of microglia. In contrast, infiltrating peripheral leukocytes were correlated with the extent of injury in hypertension [237], demonstrating the detrimental function of periphery-derived mononuclear phagocytes. The involvement of mononuclear phagocytes in hypertension-induced exacerbation of stroke outcomes and mortality suggests an immunological explanation for this risk factor.…”

Leukocyte Count and Adverse Clinical Outcomes in Acute Ischemic Stroke Patients

“…As for the effect of diabetes, the explanation is that diabetes involves chronic systemic low-grade inflammation manifested by reactive oxygen species generation, proinflammatory cytokines expression, and other inflammatory mediator activation (28). The finding surrounding hypertension could be explained by increased numbers and activation status of circulating myeloid leukocytes and increased levels of leukocyte-attracting chemokines (13).…”

“…It is reported that in the experimental mouse model of diabetes, acute inflammatory responses are perturbed in the brain following stroke, and the alteration is associated with the exacerbation of stroke-induced injury (12). Moreover, an animal experiment observes that pre-existing hypertension causes larger stroke sizes possibly as consequence of a profound increase of post-stroke inflammation (13).…”

Concise Review: Increasing the Validity of Cerebrovascular Disease Models and Experimental Methods for Translational Stem Cell Research

“…Important risk factors for stroke such as arterial hypertension or hyperlipidemia cause a chronic activation of the innate and adaptive arm of the immune system. These changes successively disrupt vascular function leading to cerebral small vessel disease and atherosclerosis . Moreover, a pre‐activated immune system aggravates stroke severity and outcome .…”