Microvascular disease, or small-vessel disease, is a multisystem disorder with a common pathophysiological basis that differentially affects various organs in some patients. The prevalence of small-vessel disease in the heart has been found to be higher in women compared with men. Additionally, other diseases prominently affecting women, including heart failure with preserved ejection fraction, Takotsubo cardiomyopathy, cerebral small-vessel disease, preeclampsia, pulmonary arterial hypertension (PAH), endothelial dysfunction in diabetes, diabetic cardiomyopathy, rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis, may have a common etiologic linkage related to microvascular disease. To the best of our knowledge this is the first article to investigate this potential linkage. We sought to identify various diseases with a shared pathophysiology involving microvascular/endothelial dysfunction that primarily affect women, and their potential implications for disease management. Advanced imaging technologies, such as magnetic resonance imaging and positron-emission tomography, enable the detection and increased understanding of microvascular dysfunction in various diseases. Therapies that improve endothelial function, such as those used in PAH, may also be associated with benefits across the full spectrum of microvascular dysfunction. A shared pathology across multiple organ systems highlights the need for a collaborative, multidisciplinary approach among medical subspecialty practitioners who care for women with small-vessel disease. Such an approach may lead to accelerated research in diseases that affect women and their quality of life.

One key signaling pathway known to influence neuronal migration involves the extracellular matrix protein Reelin. Typically, signaling of Reelin occurs via apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR), and the cytoplasmic adapter protein disabled 1 (Dab1). However, non-canonical Reelin signaling has been reported, though no receptors have yet been identified. Cariboni et al. (2005) indicated Dab1-independent Reelin signaling impacts gonadotropin releasing hormone-1 (GnRH) neuronal migration. GnRH cells are essential for reproduction. Prenatal migration of GnRH neurons from the nasal placode to the forebrain, juxtaposed to olfactory axons and olfactory ensheathing cells (OECs), has been well documented, and it is clear that alterations in migration of these cells can cause delayed or absent puberty. This study was initiated to delineate the non-canonical Reelin signaling pathways used by GnRH neurons. Chronic treatment of nasal explants with CR-50, an antibody known to interfere with Reelin homopolymerization and Dab1 phosphorylation, decreased the distance GnRH neurons and OECs migrated. Normal migration of these two cell types was observed when Reelin was co-applied with CR-50. Immunocytochemistry was performed to determine if OECs might transduce Reelin signals via the canonical pathway, and subsequently indirectly altering GnRH neuronal migration. We show that in mouse: (1) both OECs and GnRH cells express ApoER2, VLDLR and Dab1, and (2) GnRH neurons and OECs show a normal distribution in the brain of two mutant reeler lines. These results indicate that the canonical Reelin pathway is present in GnRH neurons and OECs, but that Reelin is not essential for development of these two systems in vivo.

The Dopamine D4 receptor regulates gonadotropin-releasing hormone neuron excitability in male mice. Abbreviated Title (50 character maximum)Dopamine D4 receptor-mediated inhibition of GnRH neurons 3. List all Author Names and Affiliations in order as they would appear in the published article