BACKGROUND:The cardiac hormone ANP (atrial natriuretic peptide) maintains intravascular volume homeostasis through coordinated endothelial and renal effects. Since in vitro studies suggested that this circuit involves the inhibition of adrenal aldosterone release, here we investigated whether ANP indeed mediates endocrine heart-to-adrenal communication in vivo. METHODS:Mouse models with zona glomerulosa (ZG)-restricted deletion knockout of the ANP receptor, GC-A (guanylyl cyclase-A), or the downstream cyclic GMP-stimulated PDE (phosphodiesterase) 2A were established through Cre/LoxP technology. RESULTS:Immunoblots and immunohistochemistry demonstrated high expression of GC-A and PDE2A in ZG cells. Cell-specific deletion of GC-A led to mildly expanded ZG, with more aldosterone synthase-expressing cells and elevated plasma aldosterone. While in control mice a high-salt diet reduced ZG thickness and aldosterone production, in their ZG GC-A knockout littermates these responses were blunted, provoking hypervolemic hypertension. Notably, ZG PDE2A knockout mice did not exhibit such alterations. In cultured human adrenal cells, ANP counteracted the stimulatory effects of Angiotensin II on aldosterone synthase expression and cell proliferation pathways through activation of cGMP-dependent protein kinase I. Notably, in human aldosterone-producing adrenal adenomas, the expression of GC-A was markedly lower than in healthy adrenal cortical tissue, suggesting reduced ANP/GC-A signaling in the tumor cells. CONCLUSIONS:ANP-mediated heart-adrenal communication moderates ZG cell growth and aldosterone release and participates in the inhibitory effects of dietary salt/volume load. Conversely, impaired ANP/cGMP signaling leads to excessive ZG cell growth and aldosterone production. Reinforcing this pathway with novel antibody- or peptide-based therapies may benefit patients with hyperaldosteronism and resistant hypertension.
BACKGROUND:Hypertension is a major cardiovascular risk factor with an incompletely understood cause. We aimed to unravel its proteomic landscape and investigate potential molecular mechanisms underlying its risk related to modifiable exposures. METHODS:Leveraging protein quantitative trait loci from 3 biobank-scale studies (deCODE, Fenland, and UKB-PPP [UK Biobank Pharma Proteomics Project]) based on distinct proteomic platforms (SomaScan or Olink), we performed proteome-wide Mendelian randomization to identify and cross-platform validate proteins causally associated with hypertension and blood pressure (BP). Bayesian colocalization was applied to detect shared causal variants underpinning the identified associations. A broad range of modifiable risk factors were systematically assessed for their causal associations with hypertension/BP, followed by mediation analyses exploring potential proteomic pathways linking risk factors to hypertension/BP. RESULTS:The discovery Mendelian randomization analyses (deCODE) identified 190 significant causal associations between 118 proteins and hypertension/BP, which were overall consistent in the cross-platform replication analyses (Fenland and UKB-PPP). Fifty-four protein-hypertension/BP pairs were further supported by genetic colocalization. Triangulation of evidence from Mendelian randomization and colocalization prioritized 28 proteins as key causal signatures. Among these, 10 proteins (particularly ALDH2 [mitochondrial aldehyde dehydrogenase] and ULK3 [serine/threonine-protein kinase]) were found to mediate the associations of 8 genetically predicted modifiable risk factors with hypertension/BP, with ALDH2 emerging as a central hub across multiple causal pathways. CONCLUSIONS:This study systematically characterized the causal proteomic landscape of hypertension and highlighted proteins implicated in its modifiable risk. These findings provide novel insights into the molecular cause of hypertension and identify promising candidates for further therapeutic investigation.
The brain's vasculature-from pial arteries through penetrating arterioles and the capillary bed to venous drainage-is enveloped by a narrow, compositionally elaborate perivascular space that provides the primary signaling interface between neural tissue and blood vessels. Here, we advance the principle that the geometry and composition of this space are not constant but change systematically along the vascular tree, and that perivascular space composition at these locations imposes biophysical constraints that dictate the fidelity and gain of neurovascular signaling. We argue that its narrow micro-to-nanodomain geometry, basement membrane sieving effects, and the anionic environment created by heparan sulfate proteoglycans favor small aqueous mediators-potassium, nitric oxide (NO), and adenosine-for rapid, spatially targeted blood flow control, while constraining lipophilic mediators, such as prostaglandins and epoxyeicosatrienoic acids, toward predominantly autocrine action. Reassessing glymphatic fluid flux as a proposed source of vascular mechanical input, we find that the relevant shear forces fall several orders of magnitude below the threshold required to engage canonical smooth muscle mechanotransduction, arguing against a direct mechanical role for perivascular flow. We then synthesize how hypertension degrades each layer of this system: perivascular space expansion dilutes mediator concentrations, barrier breakdown admits plasma proteins capable of sequestering signaling molecules, and inflammation dysregulates the vascular ion channels that serve as signaling effectors. Framing the perivascular space as a biophysically constrained signaling compartment helps reconcile disparate observations of mediator selectivity and fluid mechanics, identifies how its progressive disruption may contribute to cerebrovascular dysfunction associated with chronic hypertension, and may help identify novel targets for preventing or reversing cognitive decline and neurodegeneration.
Loop diuretics are first-line therapy for hypervolemia. They block the sodium-potassium-2-chloride cotransporter type 1 on the renal afferent arteriole that mediates vasoconstriction and the sodium-potassium-2-chloride cotransporter type 2 on the macula densa cells that mediates the tubuloglomerular feedback response and raises intrarenal pressure that inhibits the myogenic response. These should reduce afferent arteriolar vasoconstriction and increase the glomerular filtration rate; however, more often, the glomerular filtration rate is reduced. This has been attributed to diuretic-induced extracellular volume depletion that activates a systemic neurohormonal response. Accordingly, a fall in glomerular filtration rate can lead to strategies to restore body fluid volumes while reducing the diuretic dosage. Here, we review the regulation of renal hemodynamics during loop diuretic therapy. We propose that a passive, obstructive component of reduced renal blood flow combines with activation of renal afferent nerves, macula densa-derived renin release with intrarenal Ang II (angiotensin II) formation, and generation of vasoconstrictor prostaglandins and thromboxane to provide intrarenal mechanisms of passive and active increases in renal vascular resistance that together can reduce the glomerular filtration rate. The hypothesis that a reduction in the glomerular filtration rate with loop diuretics can derive from intrarenal mechanisms of vasoconstriction rather than from volume depletion suggests novel approaches to manage diuretic resistance and worsening renal function in heart failure.
