The authors frame cavernous endothelial cells as bidirectional regulators. They act as biomechanical sensors that detect hemodynamic forces, and as vasomotor effectors that release nitric oxide to control vascular tone. When shear stress is detected, endothelial nitric oxide synthase (eNOS) is activated through cascading signaling pathways, producing nitric oxide, which diffuses to neighboring smooth muscle cells, stimulates soluble guanylate cyclase, raises cyclic GMP, and triggers protein kinase G–mediated relaxation. Arterial inflow increases, the sinusoidal spaces expand, and the subalbugineal venous plexus is compressed, restricting outflow. The result is erection. Disruption of the mechanical sensing apparatus, the review proposes, may therefore be a root cause of vascular erectile dysfunction, a condition linked to diabetes, hypertension, atherosclerosis, and aging.

Shear stress in hemodynamics is the tangential force exerted by blood flow friction on the endothelial surface. Its magnitude depends chiefly on flow velocity and vessel caliber, and can be estimated with the wall shear stress relation derived from the Hagen-Poiseuille solution, in which shear scales with blood viscosity and volumetric flow rate and falls steeply as vessel radius grows. In straight large arteries, time-averaged wall shear stress is roughly 20 to 40 dyn/cm², whereas venous shear stress is only 1 to 2 dyn/cm². The review is careful to note, however, that these values come from systemic arterial measurements: direct measurements of fluid shear stress inside the cavernous sinusoids have not been reported, and applying arterial values to the corpus cavernosum is an extrapolation. The closest human evidence is the demonstration that shear stress mediates vasodilation of the cavernous arteries.

The cavernous microcirculation is anatomically unlike any large vessel. The corpus cavernosum is a reticular network of irregular, interconnected sinusoidal lacunae. Blood jets from high-resistance helicine arteries into low-resistance, expansive sinusoidal spaces, and the abrupt channel dilation combined with the geometric tortuosity of the sinusoidal walls produces decelerated flow, flow separation, and transient vortices. During most of the erectile cycle the sinusoids behave as a low-flow, quasi-venous compartment, so arterial shear magnitudes cannot simply be assumed to act on sinusoidal endothelium. The result is a dynamic, spatially heterogeneous mechanical environment that demands exquisite mechanosensitivity from cavernous endothelial cells, which must discriminate physiological laminar stimuli from pathological disturbances.

Shear stress within the corpus cavernosum also fluctuates in a characteristic step-like pattern across the erectile cycle. At initiation, neural signaling triggers rapid arterial dilation and a surge in flow velocity within milliseconds, subjecting endothelial cells to an intense transient shear pulse whose absolute amplitude in the sinusoids has never been directly measured. This mechanical impulse is proposed to act as the central trigger for mechano-chemical transduction, rapidly inducing conformational shifts in mechanoreceptors such as the glycocalyx and Piezo1 channels and activating eNOS phosphorylation. As erection progresses to the maintenance and rigidity phases, compression of the venous plexus raises intracavernous pressure, flow velocity falls, and shear stress drops to a stabilized low plateau. At this point the dominant mechanical cue shifts from tangential shear to vertical hydrostatic pressure, and the endothelial cell is hypothesized to switch from active signal transduction to barrier maintenance.

The review then catalogues the molecular mechanosensors. The endothelial glycocalyx, a carbohydrate-rich mesh of proteoglycans and glycosaminoglycans covering the apical surface, is the first physical structure to contact flowing blood. Heparan sulfate accounts for 50 to 90 percent of its glycosaminoglycans, and deformation of its long chains is thought to transmit mechanical energy to the cytoskeleton and transmembrane proteins such as PECAM-1, triggering downstream eNOS activation. Primary cilia, single tubular organelles projecting from the cell surface, are considered sensors highly sensitive to low-intensity shear, working with the polycystin-1/2 complex to regulate intracellular calcium. Piezo1, a non-selective cation channel with a distinctive three-bladed paddle structure, opens in response to membrane tension and mediates a surge of extracellular calcium that activates eNOS via the calcium–calmodulin complex. Functional Piezo1 has been demonstrated in rat cavernosal tissue and the pudendal artery, and shear-stress-induced nitric oxide production has been shown in cultured human cavernous endothelial cells. By contrast, the PECAM-1/VE-cadherin/VEGFR2 mechanosensory complex, TRPV4 channels, and primary cilia have been characterized in other endothelial types, and their operation in cavernous endothelial cells, while mechanistically plausible, remains to be demonstrated directly.

Pathological conditions reshape this mechanical system in distinct ways, the review argues. In atherosclerosis, plaques alter the luminal morphology of the cavernous arteries, shifting flow from steady laminar patterns to disturbed, turbulent regimes with regions of low shear stress, typically below 4 dyn/cm², and oscillatory shear. In systemic arteries, laminar flow induces the atheroprotective transcription factors KLF2 and KLF4, which suppress inflammatory programs and maintain eNOS expression, while disturbed flow removes this brake and drives endothelial cells toward a pro-inflammatory, vasoconstrictive, and proliferative phenotype. These transcriptional findings are established in systemic and coronary endothelium and are presumed, but unproven, to apply to cavernous cells. In hypertension, microvascular remodeling and high-frequency pulsatile loading chronically overactivate Piezo1, producing calcium overload, oxidative stress, depletion of the eNOS cofactor BH4, and eNOS uncoupling — a well-established axis in systemic vascular biology that remains inferred rather than proven in cavernosal endothelium.

Diabetes attacks the sensing apparatus at multiple levels. Hyperglycemia-derived advanced glycation end products degrade the glycocalyx, cross-link the extracellular matrix and increase its stiffness, and generate reactive oxygen species that disrupt PECAM-1 complex signaling, uncouple eNOS, and scavenge nitric oxide. Notably, hyperglycemia has been shown to directly inhibit shear-induced nitric oxide production in human cavernosal endothelial cells. Aging acts more gradually: the proportion of smooth muscle in the corpus cavernosum declines while collagen cross-linking increases, shifting the tissue from high elasticity to high stiffness. The glycocalyx thins with age in multiple vascular beds, oxidative stress rearranges the actin cytoskeleton and raises intrinsic cellular stiffness, and the frequency of shear-induced calcium influx falls in aged endothelial cells. The authors hypothesize that this raises the activation threshold of mechanosensors such as Piezo1, blunting the endothelium’s response to the initial flow pulse of erection. They also caution that cause and consequence are difficult to separate: impaired mechanotransduction may contribute to erectile dysfunction directly, or arise secondarily once cavernosal blood flow declines, with the two processes most plausibly reinforcing each other in a vicious cycle.

Methodologically, the review is candid about the limits of the field. Most conclusions about endothelial mechanosensing derive from two-dimensional parallel-plate flow chambers or cone-plate viscometers, which cannot replicate the three-dimensional, porous, elastic sinusoidal network of the corpus cavernosum or the unique coupling of transient high shear with sustained high hydrostatic pressure during erection. The authors call for a cavernosum-on-a-chip: a microfluidic platform integrating a three-dimensional matrix of adjustable stiffness, co-cultured primary cavernous endothelial and smooth muscle cells, and pulsatile flow. Complementary tools are already available, including single-cell RNA sequencing of human cavernosal tissue, atomic force microscopy for nanoscale stiffness measurement, and FRET tension sensors engineered into PECAM-1 and VE-cadherin that visualize molecular forces in living cells.

The translational implications are striking. Shear-wave elastography could shift diagnosis from flow-velocity monitoring toward quantitative tissue biomechanical assessment, potentially detecting vascular erectile dysfunction earlier than conventional ultrasound indices. On the therapeutic side, the mechanosensory axis appears druggable at several levels: sulodexide partially restored glycocalyx dimensions in patients with type 2 diabetes, the Piezo1 agonist Yoda1 relaxes cavernosal tissue ex vivo, and low-intensity extracorporeal shockwave therapy improved erectile function scores and penile endothelial function at six-month follow-up in a pilot study of men with organic erectile dysfunction. Low-intensity pulsed ultrasound, which regulates cell fate through Piezo1, integrin, and calcium signaling, is advancing rapidly in regenerative medicine. If the hypotheses laid out in this review withstand direct experimental testing in cavernous tissue, erectile dysfunction may come to be understood — and treated — not merely as a chemical deficiency, but as a failure of the body’s ability to hear the force of its own blood.

Subject of Research: Mechanotransduction of fluid shear stress in corpus cavernosum endothelial cells and its role in vascular erectile dysfunction

Article Title: Recent advances in research on the force transmission mechanisms regulating endothelial function in the corpus cavernosum via fluid shear stress

Article References: Wu, Y., Hu, J., Lin, Z., Xu, R., Chen, Z., Xie, L., Chen, M., Wu, Z., Zhang, Q., Lu, C., & Lv, B. (2026). Recent advances in research on the force transmission mechanisms regulating endothelial function in the corpus cavernosum via fluid shear stress. Frontiers in Physiology, 17, Article 1949178. https://doi.org/10.3389/fphys.2026.1949178

Image Credits: AI Generated

DOI: 10.3389/fphys.2026.1949178

Keywords: fluid shear stress, endothelial cells, corpus cavernosum, erectile dysfunction, mechanotransduction, Piezo1, glycocalyx, eNOS, nitric oxide, atherosclerosis, diabetes, shockwave therapy