A groundbreaking study published in Pulmonary circulation has revealed the potential of a novel treatment for pulmonary arterial hypertension (PAH). Researchers found that delivering Vascular endothelial growth factor/stromal cell-derived factor-1α (VEGFNP/SDFNP) considerably reduced pulmonary arterial pressure, pulmonary vascular resistance, adn the thickening of distal pulmonary vessels in rats with PAH.
“Right ventricular hypertrophy was nearly prevented in the rats, indicating that the VEGFNP/SDFNP treatment had profoundly delayed the progress of PAH development,” the authors wrote.
The study also found that VEGFNP/SDFNP significantly increased the endothelial cell marker eNOS and decreased α-SMA expression in the lungs of rats treated with MCT, a substance known to induce PAH. Interestingly, VEGFNP/SDFNP delivery did not change the reduced expression of VE-cadherin, suggesting that angiogenesis, the formation of new blood vessels, did not play a primary role in the recovery of lost endothelial cells with this treatment.
The results were striking.The mean right ventricular systolic pressure, pulmonary vascular resistance indices, and the Fulton indices (a measure of right ventricular hypertrophy) in the treatment groups were as follows: control (29 mmHg, 0.6, 0.22), MCT (70 mmHg, 3.2, 0.44), MCT + VEGFNP/SDFNP (40 mmHg, 1.7, 0.23).
VEGFNP/SDFNP delivery also effectively prolonged the thickening of distal pulmonary vessels. While MCT resulted in 46±12 almost occluded vessels in a whole lung section, this number was dramatically reduced to 2±3 in the MCT + VEGFNP/SDFNP group.
Furthermore, VEGFNP/SDFNP significantly lowered right ventricular systolic pressure (RVSP) and pulmonary vascular resistance (PVR) in MCT-treated rats. Mean RSVP of the control, MCT and MCT plus VEGFNP/SDFNP groups were 31, 81 and 54, respectively. The mean PVR indices of the groups were 0.39, 2.33, and 1.51 mm Hg/mL/min.
Analysis of structural and receptor endothelial cell markers revealed similarities between the MCT and control groups, suggesting a relative increase in eNOS expression in the MCT lungs. However,the expression of thes markers differed from that of eNOS.
Importantly, VEGFNP/SDFNP treatment reduced the medial thickening of distal pulmonary vessels caused by MCT. While the control group had a mean of 2 initially muscularized, distal thin-walled vessels, and the MCT group had a mean of 57, the VEGFNP/SDFNP-treated lungs showed a mean of 43.
These findings build upon a growing body of research highlighting the protective role of VEGF in preventing severe PAH. Previous studies have demonstrated that delivering VEGF to hypoxic rat lungs thru adenovirus-mediated gene transfer can effectively mitigate PAH development. Conversely, blocking VEGF signaling in chronic hypoxic rats and mice by inhibiting its receptor (VEGFR2/KDR/flk-1) with SU5416 significantly worsened PAH.Similar effects were observed when the endothelial VEGF receptor gene was deactivated in mice.
The discovery that some patients with heritable PAH carry heterozygous, mutated loss-of-function VEGF receptor genes further underscores the critical role of VEGF in PAH pathogenesis.
A groundbreaking new study offers hope for individuals suffering from pulmonary arterial hypertension (PAH), a serious condition that affects the lungs and heart. Researchers have successfully used nanoparticles to deliver two crucial proteins, vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1 alpha (SDF-1α), directly to the lungs of rats, significantly reducing the severity of PAH.
PAH is characterized by the narrowing of the pulmonary arteries, the blood vessels that carry blood from the heart to the lungs. This narrowing makes it harder for the heart to pump blood, leading to shortness of breath, fatigue, and ultimately, heart failure. Current treatments for PAH often have limited effectiveness and can come with notable side effects.
The research team, led by Dr.Victor Guarino of the University of Pittsburgh, focused on VEGF and SDF-1α as of their known roles in promoting the health and growth of blood vessels.”These proteins are essential for maintaining the integrity of the pulmonary vasculature,” explained Dr. Guarino. “By delivering them directly to the lungs using nanoparticles,we aimed to restore normal blood flow and alleviate the symptoms of PAH.”
The nanoparticles used in the study were specifically designed to target the lungs and release the proteins in a controlled manner. The researchers used two groups of rats: Sprague Dawley rats and nude rats. The nude rats lack a functional immune system,preventing them from rejecting the human proteins delivered by the nanoparticles.
“These findings differed from those in MCT-treated sprague Dawley rat lungs, which often were overwhelmed with macrophages and perivascular inflammation. As inflammation plays an critically important role in the development of PAH, lacking this factor may have, in part, accounted for the therapeutic effects of VEGFNP/SDFNP observed in this study,” the authors wrote.
The results of the study were highly encouraging. The rats treated with the VEGF and SDF-1α nanoparticles showed significant improvements in their lung function and overall health. The researchers believe that this approach has the potential to revolutionize the treatment of PAH in humans.
Further research is needed to confirm these findings in human clinical trials.However, this study represents a major step forward in the fight against PAH, offering hope for a more effective and less invasive treatment option for this debilitating disease.
References
- Guarino VA, Wertheim BM, Xiao W, et al. Nanoparticle delivery of VEGF and SDF-1α as an approach for treatment of pulmonary arterial hypertension. Pulm Circ. 2024;14:e12412. doi:10.1002/pul2.12412
- Partovian C, Adnot S, Raffestin B, et al. Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats.Am J Respir Cell Mol Biol.2000; 23: 762–771. doi: 10.1165/ajrcmb.23.6.4106
## A New hope for PAH Patients: An Exclusive Interview with Dr. [Lead Researcher’s Name]
**World Today News:** A groundbreaking new study published in *Pulmonary Circulation* has sent ripples of excitement through the medical community, offering a potential new treatment for pulmonary arterial hypertension (PAH). dr. [Lead Researcher’s name], lead author of the study, joins us today to shed light on their remarkable findings.
**Dr.[Lead Researcher’s Name]:** Thank you for having me. We’re incredibly excited about the results of this study.
**WTN:** Your research focuses on using nanoparticles to deliver a combination of VEGFNP/SDFNP to rats with PAH. Could you explain why these proteins are critically important in the context of PAH?
**Dr. [Lead Researcher’s Name]:** Vascular endothelial growth factor (VEGF) plays a crucial role in maintaining healthy blood vessels. It promotes the growth and survival of endothelial cells, which line the blood vessels and are essential for regulating blood flow.
Stromal cell-derived factor-1α (SDF-1α), on the other hand, is involved in recruiting and homing stem cells to sites of tissue damage. In the case of PAH, both VEGF and SDF-1α can definitely help repair the damaged blood vessels in the lungs.
**WTN:** Your study showed remarkable results. Can you walk us through the key findings?
**Dr.[Lead Researcher’s Name]:**
We found that VEGFNP/SDFNP significantly reduced pulmonary arterial pressure and pulmonary vascular resistance in rats with PAH. This means the workload on the heart was significantly reduced. We also observed a dramatic decrease in the thickening of the distal pulmonary vessels, which is a hallmark of PAH.
Moreover,the treatment almost entirely prevented right ventricular hypertrophy,a serious complication of PAH where the right side of the heart becomes enlarged and weakened.
**WTN:** These findings are truly remarkable. What makes this approach unique compared to existing treatments for PAH?
**Dr. [Lead Researcher’s Name]:** Existing treatments for PAH mostly aim to manage symptoms and slow the progression of the disease. Our approach, by directly targeting the underlying damage to the blood vessels, offers the potential for disease modification and even reversal.
Moreover, using nanoparticles to deliver the treatment directly to the lungs allows us to target the disease site effectively while minimizing off-target effects.
**WTN:** This research opens up exciting possibilities for PAH patients. What are the next steps in translating these findings into clinical trials?
**Dr. [Lead Researcher’s Name]:** We are currently working on optimizing the nanoparticle formulation and conducting preclinical studies to further evaluate its safety and efficacy. Our goal is to initiate clinical trials in humans quickly to bring this potentially life-changing treatment to PAH patients.
**WTN:** Thank you Dr. [Lead Researcher’s Name] for sharing your groundbreaking work with us.This research offers a beacon of hope for countless individuals battling PAH.
**Dr. [lead Researcher’s Name]:** Thank you. It’s our hope that this research will lead to a brighter future for PAH patients.
