Inmaculada Villar

Sex differences in vascular function: implication of endothelium-derived hyperpolarizing factor

The vascular endothelium plays a crucial role in the regulation of vascular homeostasis by controlling vascular tone, coagulation, and inflammatory responses. These actions are exerted by endothelial factors including nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). The greater incidence of cardiovascular disease (CVD) in men and postmenopausal women compared with premenopausal women implies a vasoprotective phenotype of females, which may be influenced by sex hormones. These hormones, particularly estrogen, have modulatory effects on the endothelium and circulating cells that have been implicated in vascular inflammation and in the development of CVD. EDHF seems to be the predominant endothelial factor in the resistance vasculature of females and this mediator could afford the beneficial cardiovascular risk profile observed in premenopausal woman. In this review, we discuss sex differences in EDHF biology and how sex hormones can modulate EDHF responses. We also review the implication of sex hormone-dependent regulation of EDHF in inflammatory processes, platelet function, and repair after vascular damage, each of which have a critical role in several aspects of the pathogenesis of CVD.

Endothelial C-type natriuretic peptide maintains vascular homeostasis

The endothelium plays a fundamental role in maintaining vascular homeostasis by releasing factors that regulate local blood flow, systemic blood pressure, and the reactivity of leukocytes and platelets. Accordingly, endothelial dysfunction underpins many cardiovascular diseases, including hypertension, myocardial infarction, and stroke. Herein, we evaluated mice with endothelial-specific deletion of Nppc, which encodes C-type natriuretic peptide (CNP), and determined that this mediator is essential for multiple aspects of vascular regulation. Specifically, disruption of CNP leads to endothelial dysfunction, hypertension, atherogenesis, and aneurysm. Moreover, we identified natriuretic peptide receptor-C (NPR-C) as the cognate receptor that primarily underlies CNP-dependent vasoprotective functions and developed small-molecule NPR-C agonists to target this pathway. Administration of NPR-C agonists promotes a vasorelaxation of isolated resistance arteries and a reduction in blood pressure in wild-type animals that is diminished in mice lacking NPR-C. This work provides a mechanistic explanation for genome-wide association studies that have linked the NPR-C (Npr3) locus with hypertension by demonstrating the importance of CNP/NPR-C signaling in preserving vascular homoeostasis. Furthermore, these results suggest that the CNP/NPR-C pathway has potential as a disease-modifying therapeutic target for cardiovascular disorders.

Distinct endothelial pathways underlie sexual dimorphism in vascular auto-regulation

BACKGROUND AND PURPOSE Pre‐menopausal females have a lower incidence of cardiovascular disease compared with age‐matched males, implying differences in the mechanisms and pathways regulating vasoactivity. In small arteries, myogenic tone (constriction in response to raised intraluminal pressure) is a major determinant of vascular resistance. Endothelium‐derived dilators, particularly NO, tonically moderate myogenic tone and, because the endothelium is an important target for female sex hormones, we investigated whether NO‐mediated moderation of myogenic tone differed between the sexes.

Suppression of Endothelial P-Selectin Expression Contributes to Reduced Cell Trafficking in Females: An Effect Independent of NO and Prostacyclin

Objective—Sex hormones underlie the lower incidence of cardiovascular disease in premenopausal women. Vascular inflammation is involved in the pathogenesis of several cardiovascular diseases and it has been reported that sex hormones modulate inflammatory responses but mechanisms responsible for these effects are not yet fully established. Herein, we assessed whether sex differences in leukocyte recruitment might exist and investigated the underlying mechanisms involved in this response. Methods and Results—Treatment with interleukin-1&bgr; (IL-1&bgr;) or tumor necrosis factor-&agr; caused leukocyte rolling, adhesion, and emigration in mesenteric postcapillary venules in vivo that was substantially reduced in female mice compared with male mice; this difference was abolished by ovariectomy and partially restored by estrogen replacement. Deletion of endothelial nitric oxide (NO) synthase or cyclooxygenase-1 alone or in combination did not alter the leukocyte recruitment in IL-1&bgr;-treated females but significantly enhanced this response in male mice. Treatment of murine pulmonary endothelial cells with IL-1&bgr; increased expression of P-selectin in male but not female cells. Conclusion—We have demonstrated a profound estrogen-dependent and NO and prostacyclin-independent suppression of leukocyte recruitment in females.

Functional pharmacological characterization of SER100 in cardiovascular health and disease

SER100 is a selective nociceptin (NOP) receptor agonist with sodium‐potassium‐sparing aquaretic and anti‐natriuretic activity. This study was designed to characterize the functional cardiovascular pharmacology of SER100 in vitro and in vivo, including experimental models of cardiovascular disease.

Characterisation of preproendothelin-1 derived peptides identifies Endothelin-Like Domain Peptide as a modulator of Endothelin-1.

Endothelin-1 (ET-1) is involved in the pathogenesis of cardiac and renal diseases, and in the progression of tumour growth in cancer, but current diagnosis and treatment remain inadequate. Peptides derived from the 212 amino acid precursor preproendothelin-1 (ppET-1) may have utility as biomarkers, or cause biological effects that are unaffected by endothelin receptor antagonists. Here, we used specific immunoassays and LC-MS/MS to identify NT-proET-1 (ppET-1[18–50]), Endothelin-Like Domain Peptide (ELDP, ppET-1[93–166]) and CT-proET-1 (ppET-1[169–212]) in conditioned media from cultured endothelial cells. Synthesis of these peptides correlated with ET-1, and plasma ELDP and CT-proET-1 were elevated in patients with chronic heart failure. Clearance rates of NT-proET-1, ELDP and CT-proET-1 were determined after i.v. injection in anaesthetised rats. CT-proET-1 had the slowest systemic clearance, hence providing a biological basis for it being a better biomarker of ET-1 synthesis. ELDP contains the evolutionary conserved endothelin-like domain sequence, which potentially confers biological activity. On isolated arteries ELDP lacked direct vasoconstrictor effects. However, it enhanced ET-1 vasoconstriction and prolonged the increase in blood pressure in anaesthetised rats. ELDP may therefore contribute to disease pathogenesis by augmenting ET-1 responses.

Investigation of the role of multidrug resistance proteins (MRPs) in vascular homeostasis

Cellular levels of cyclic GMP (cGMP) are tightly controlled by synthetic and degradative mechanisms. Pharmacological manipulation of these processes (e.g. soluble guanylate cyclase stimulators and phosphodiesterase 5 inhibitors) augments cGMP-dependent signalling and is beneficial in treating cardiovascular disease (eg. pulmonary hypertension). An additional mechanism potentially important in the inactivation of cGMP is cellular extrusion, driven by a family of multidrug resistance proteins (MRPs). Herein, we investigated if MRPs modulate vascular reactivity, smooth muscle cell proliferation, and systemic hemodynamics. The functional reactivity of murine aortic rings and proliferation of human pulmonary artery smooth muscle cells (PASMC) were determined in the absence and presence of the MRP inhibitor MK571. Hemodynamic changes in vivo in response to MK571 were analysed acutely by bolus dosing and chronically by radiotelemetry. MK571 (1nM-50µM) caused a concentration-dependent relaxation of mouse aortic r...