Background: Cerebral small vessel disease (cSVD), a common risk factor for cognitive impairment, involves unspecific arteriopathy characterized by hypertrophy and endothelial dysfunction that alter cerebrovascular function and auto-regulation of cerebral blood flow (CBF). Microbleedings, subcortical lacunar infarctions and diffuse areas of white matter lesions resulting from vascular injury are associated with reduced cognitive function mostly characterized by difficulties in learning and retention, attention deficits, gait disorders or depression. In recent years, it has become evident that vascular risk factors contribute to the development of cSVD and associated vascular cognitive impairment (VCI). Among them, hypertension emerged as such a major modifiable risk factor since the brain presents an early target for organ damage due to changes in blood pressure (BP). Subsequently both high and, especially in the elderly, low BP have been linked to cognitive decline, which initiated controversial discussions about BP control as a potential therapeutic strategy to achieve optimal brain perfusion and thus, reduce the occurrence of cSVD and cognitive dysfunction. Yet, recent randomized controlled trials examined the impact of anti-hypertensive therapy on cognitive performance with conflicting results. Summary: In light of the current knowledge, it becomes apparent that there is an urgent need to understand the mechanisms underlying hypertension-induced cerebrovascular complications in order to identify effective therapeutic targets to prevent and most importantly also reverse cognitive decline mediated through hypertension. Key Message: This review summarizes the current knowledge of cSVD pathogenesis as well as possible links to hypertension-mediated cerebrovascular complications. By pointing out knowledge gaps, it aims to spur future studies in search of specific targets helping to prevent therapy failures and decelerate the rapidly progressing neuro-degeneration of patients suffering from cerebrovascular diseases emanating from hypertension.

The glymphatic system is a highly polarized cerebrospinal fluid (CSF) transport system that facilitates the clearance of neurotoxic molecules through a brain-wide network of perivascular pathways. Herein we have mapped the development of the glymphatic system in mice. Perivascular CSF transport first emerges in hippocampus in newborn mice, and a mature glymphatic system is established in the cortex at 2 weeks of age. Formation of astrocytic endfeet and polarized expression of aquaporin 4 (AQP4) consistently coincided with the appearance of perivascular CSF transport. Deficiency of platelet-derived growth factor B (PDGF-B) function in the PDGF retention motif knockout mouse line Pdgfbret/ret suppressed the development of the glymphatic system, whose functions remained suppressed in adulthood compared with wild-type mice. These experiments map the natural development of the glymphatic system in mice and define a critical role of PDGF-B in the development of perivascular CSF transport.

Rationale:: Mechanisms underlying vasomotor abnormalities and increased peripheral resistance exacerbating heart failure (HF) are poorly understood. Objective:: To explore the role and molecular basis of myogenic responses in HF. Methods and Results:: 10 weeks old C57Bl6 mice underwent experimental myocardial infarction (MI) or sham surgery. At 1 to 12 weeks postoperative, mice underwent hemodynamic studies, mesenteric, cerebral, and cremaster artery perfusion myography and Western blot. Organ weights and hemodynamics confirmed HF and increased peripheral resistance after MI. Myogenic responses, ie, pressure-induced vasoconstriction, were increased as early as 1 week after MI and remained elevated. Vasoconstrictor responses to phenylephrine were decreased 1 week after MI, but not at 2 to 6 weeks after MI, whereas those to endothelin (ET)-1 and sphingosine-1-phosphate (S1P) were increased at all time points after MI. An antagonist (JTE-013) for the most abundant S1P receptor detected in mesenteric arteries (S1P ₂ R) abolished the enhanced myogenic responses of HF, with significantly less effect on controls. Mice with genetic absence of sphingosine-kinases or S1P ₂ R ( Sphk1 ^−/− ; Sphk1 ^−/− /Sphk2 ^+/− ; S1P ₂ R ^−/− ) did not manifest enhanced myogenic responses after MI. Mesenteric arteries from HF mice exhibited increased phosphorylation of myosin light chain, with deactivation of its phosphatase (MLCP). Among known S1P-responsive regulators of MLCP, GTP-Rho levels were unexpectedly reduced in HF, whereas levels of activated p38 MAPK and ERK1/2 (extracellular signal-regulated kinase 1/2) were increased. Inhibiting p38 MAPK abolished the myogenic responses of animals with HF, with little effect on controls. Conclusions:: Rho-independent p38 MAPK-mediated deactivation of MLCP underlies S1P/S1P ₂ R-regulated increases in myogenic vasoconstriction observed in HF. Therapeutic targeting of these findings in HF models deserves study.

Hypertension is a complex condition involving functional and structural alterations of the microvasculature and an activation of the immune system. T-lymphocytes play a crucial role during the development of hypertension in experimental models, yet the underlying mechanisms remain elusive. Lymphocyte egress from lymph nodes is controlled by sphingosine-1-phosphate (S1P), a natural lipid mediator regulating immune cell and vascular function in health and disease. We therefore investigated the involvement of S1P signalling in the pathogenesis of hypertension. Angiotensin-II (AngII) treatment resulted in high blood pressure (BP) associated to increased plasma S1P and circulating T-cell counts. T-cell egress from lymph nodes was found to be a critical initial step for the onset of hypertension as fingolimod, a S1P-receptor agonist sequestering lymphocytes in the lymph nodes and inducing lymphopenia, blunted BP responses to AngII. Furthermore, activity of S1P-generating enzyme type 2 (SphK2) in haematopoietic cells critically contributed to AngII-induced lymphocyte mobilization from the lymph nodes as SphK2^-/- mice and mice where SphK2 was ablated only in the haematopoietic system presented an accumulation of T-cells in mesenteric lymph nodes and a blunted BP response. In addition, deregulation of vascular SphK2 expression associated to a thrombo-inflammatory phenotype of the microvasculature, and to functional alterations of small resistance arteries. The presented results point to a critical involvement of S1P and its signalling axis in the pathogenesis of hypertension. Specifically, SphK2 evolves as key player in immune cell trafficking and vascular dysfunction contributing to the development of overt hypertension.